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1
Bertos, Nicholas R., Audrey H. Wang e Xiang-Jiao Yang. "Class II histone deacetylases: Structure, function, and regulation". Biochemistry and Cell Biology 79, n. 3 (1 giugno 2001): 243–52. http://dx.doi.org/10.1139/o01-032.
Testo completoAbstract (sommario):
Acetylation of histones, as well as non-histone proteins, plays important roles in regulating various cellular processes. Dynamic control of protein acetylation levels in vivo occurs through the opposing actions of histone acetyltransferases and histone deacetylases (HDACs). In the past few years, distinct classes of HDACs have been identified in mammalian cells. Class I members, such as HDAC1, HDAC2, HDAC3, and HDAC8, are well-known enzymatic transcriptional corepressors homologous to yeast Rpd3. Class II members, including HDAC4, HDAC5, HDAC6, HDAC7, and HDAC9, possess domains similar to the deacetylase domain of yeast Hda1. HDAC4, HDAC5, and HDAC7 function as transcriptional corepressors that interact with the MEF2 transcription factors and the N-CoR, BCoR, and CtBP corepressors. Intriguingly, HDAC4, HDAC5, and probably HDAC7 are regulated through subcellular compartmentalization controlled by site-specific phosphorylation and binding of 14-3-3 proteins; the regulation of these HDACs is thus directly linked to cellular signaling networks. Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions. Comprehension of the structure, function, and regulation of class II deacetylases is important for elucidating how acetylation regulates functions of histones and other proteins in vivo.Key words: histone acetylation, protein acetylation, histone deacetylase, 14-3-3 proteins.
2
Ozawa, Yukiyasu, Masayuki Towatari, Shinobu Tsuzuki, Fumihiko Hayakawa, Takahiro Maeda, Yasuhiko Miyata, Mitsune Tanimoto e Hidehiko Saito. "Histone deacetylase 3 associates with and represses the transcription factor GATA-2". Blood 98, n. 7 (1 ottobre 2001): 2116–23. http://dx.doi.org/10.1182/blood.v98.7.2116.
Testo completoAbstract (sommario):
The zinc finger transcription factor GATA-2 plays a critical role in the survival and proliferation of hematopoietic stem cells. This study examined the interaction of GATA-2 with histone deacetylases (HDACs) to define the involvement of HDACs in the regulation of GATA-2 function. GATA-2 directly associates with HDAC3 but not with HDAC1. Consistent with this, HDAC3 suppressed the transcriptional potential of GATA-2, whereas HDAC1 did not affect GATA-2–dependent transcription. Results further demonstrated that GATA-2 and HDAC3 colocalized in the nucleus. These results identify GATA-2 as a nuclear target for HDAC3-mediated repression. Furthermore, GATA-2 also directly associated with HDAC5 but not with other class II HDACs examined, that is, HDAC4 and HDAC6. This is the first demonstration that a tissue-specific transcription factor directly and selectively interacts with HDAC3 and HDAC5 among HDAC family members.
3
Stubbs, Matthew C., Won-Il Kim, Tina Davis, Jun Qi, James Bradner, Andrew L. Kung e Scott A. Armstrong. "Selective Inhibition of HDAC1 and HDAC2 Is a Potential Therapeutic Option for B-All". Blood 116, n. 21 (19 novembre 2010): 2900. http://dx.doi.org/10.1182/blood.v116.21.2900.2900.
Testo completoAbstract (sommario):
Abstract Abstract 2900 Histone deacetylase inhibitors (HDACi) have emerged as potent anticancer agents, and could open the door for future epigenetic therapies. As our understanding of the importance of epigenetic histone modifications in B-cell acute lymphoblastic leukemia (B-ALL) increases, we hypothesized that HDACi could potentially be a useful therapeutic option. The pan-HDAC inhibitor LAQ824 (Novartis) was toxic to B-ALLs in low nM concentrations in vitro, and treated cells had increased p21 and DNA damage response as indicated by increased γH2A.X protein levels. Additionally, the related compound panobinostat (Novartis) reduced leukemic burden from B-ALL patient samples in primary xenograft models, indicating that pan-HDAC inhibition is a putative B-ALL therapeutic option. To determine HDAC isoform-specific effects, we used a high throughput assay that exposed B-ALL cell lines to a panel of HDAC inhibitors. This screen indicated that tubacin, an HDAC6 specific inhibitor, cannot inhibit B-ALL cell growth within a dose range where HDAC6 is the only HDAC targeted. This finding was further validated using another HDAC6 specific inhibitor, WT-161. The screen also indicated that benzimide compounds such as MGCD-0103 (MethylGene) and MS-275 (Entinostat, Syndax) which only target class I HDACs (HDAC1-3) effectively inhibited growth in the cell lines. These data indicate that inhibiting the class I HDACs is sufficient to suppress B-ALL cell line growth. To determine which HDACs are necessary for cell viability, we lentivirally introduced isoform-specific shRNAs into our ALL cell lines. Knockdown of HDAC1 or HDAC2 resulted in p21 induction, slowed growth rate and resulted in a modest increase in apoptosis. Knockdown of HDAC3 lead to increased p21 and γH2A.X protein levels, along with induction of apoptosis, closely mimicking the results of pan-HDAC inhibitor treatment of the cells. Although depletion of HDAC3 had a more immediate impact on B-ALL viability by comparison to HDAC1/2, concerns about the contribution of HDAC3 inhibition to toxicity led us to further investigate whether specific inhibition of HDAC1/2 might be efficacious in B-ALL. Treatment of B-ALL cells with Merck 60, a tool compound with selectivity for HDAC1/2, was efficacious against was effective against B-ALL lines in the low to mid nM range. The kinetics of growth suppression were slower with this compound than with the pan-HDAC inhibitors. Using this compound, the ALL lines required 72 hours of exposure before cell growth was diminished, and apoptosis ensued. This may be due to the increased time necessary to accumulate acetylated histone marks as observable by western blot (18 hours for Merck 60 vs. 2–4 hours for LAQ824). Increased levels of p21 and γH2A.X were also observed. Interestingly, AML cell lines were much less sensitive to the HDAC1/2 specific inhibitor than were the B-ALL lines (roughly 5–10 fold), whereas pan-HDAC inhibitors were equally effective against AML and ALL. Additionally, non-hematopoietic tumor derived cell lines were insensitive to Merck 60, with EC50 values exceeding 20μM. Our findings indicate that pan-HDAC and class I specific HDAC inhibitors are possible therapeutic options for B-ALL. In contrast to most other cancer cell types studied, selective inhibition of HDAC1 and HDAC2 was sufficient to induce apoptosis in B-ALL lines. Together, these results suggest that small molecules specifically targeting HDAC1/2 may have therapeutic utility in B-ALL, and may provide improved therapeutic index by comparison to pan-HDAC or class I HDAC inhibitors that also target HDAC3. Disclosures: No relevant conflicts of interest to declare.
4
Varricchio, Lilian, Carmela Dell'Aversana, Angela Nebbioso, Giovanni Migliaccio, Lucia Altucci, James J. Bieker e Anna Rita F. Migliaccio. "Identification of a New Functional HDAC Complex Composed by HDAC5, GATA1 and EKLF in Human Erythroid Cells". Blood 120, n. 21 (16 novembre 2012): 979. http://dx.doi.org/10.1182/blood.v120.21.979.979.
Testo completoAbstract (sommario):
Abstract Abstract 979 Histone deacetylation, the reaction that maintains chromatin in a condensed configuration preventing gene expression, is catalyzed by the histone deacetylase (HDAC) superfamily. The human HDAC family includes 18 different isoforms classified on the basis of their sequence homology to HDACs from Saccharomyces Cerevisiae into class I (HDAC1, −2, −3, and −8), IIa (HDAC4, −5, −7, and −9), IIb (HDAC6 and −10) and IV (HDAC11). Class I HDACs bind the DNA directly while class IIa HDACs shuffles other proteins between nucleus and cytoplasm. While the role of individual class I HDACs in erythropoiesis is starting to emerge, that of class IIa and b HDACs is still largely unknown. To clarify the role played by class IIa HDACs in the control of human erythropoiesis, an extensive analysis of expression, activity, and function of different classes of HDACs during the maturation of erythroblasts derived in vitro from adult blood or cord blood was performed. HDACs expression/activity. Erythroid maturation was associated with increased expression of class I HDACs (both mRNA and protein) which, in the case of HDAC1, was also associated with increased enzymatic activity and association with its NuRD partner GATA1. By contrast, reductions either in expression (HDAC4) or activity (HDAC5) of class IIa HDACs were observed with maturation. In addition, GATA1 and EKLF were consistently found associated in human erythroblasts but EKLF was not found associated with HDAC1. The extent of nuclear-cytoplasmic trafficking of class I (HDAC1 and 2) and IIa (HDAC4 and 5) and of the transcription factors EKLF and GATA1 in response to EPO was determined. HDAC2/EKLF/GATA1 and HDAC4 were found constitutively present in the nucleus and in the cytoplasm, respectively. By contrast, the nuclear concentration of HDAC1 increased while that of HDAC5 and of GATA1fl decreased upon stimulation with EPO. The last two observations suggested that HDAC5, GATA1 and EKLF might be associated in a complex. Identification of the HDAC5/EKLF/GATA1 complex. A series of IPs followed by WB experiments showed that HDAC5 was consistently associated with EKLF and GATA1 and conversely, both GATA1 (preferentially GATA1fl over GATA1s) and EKLF were consistently associated with HDAC5 (Fig 1A and not shown). Interestingly also pERK was detected in IPs with HDAC5, EKLF and GATA1 antibodies. These results indicate that in erythroid cells HDAC5 forms a complex with GATA1, EKLF and pERK. Identification of the biological activity of the HDAC5/GATA1/EKLF/pERK complex. The association between GATA1/EKLF was greater in cells generated with cord blood (which express high HbF levels) than in those derived from adult blood and their association decreased with maturation, suggesting that the complex may regulate HbF expression. To confirm this hypothesis, HDAC5/GATA1 association and γ/(γ+ β) mRNA ratios were determined in erythroid cells induced to mature in the presence of a pan-class II-specific (APHA9, ID50=20 μM for HDAC4) HDAC inhibitor (HDACi) (Fig 1B)1. Cells exposed in parallel to the class I/IIa-specific (UBHA24, ID50 =0.2 and 0.6 μM for HDAC1 and HDAC4, respectively) HDACi, were used as control. Exposure to APHA9 reduced the association between GATA1 and HDAC5 and increased γ/(γ + β) mRNA expression ratio, while this association was not affected by exposure to the class I/II HDACi which, as expected, also increased γ/(γ+ β) mRNA ratio. Conclusions. These data identify a new HDAC complex formed by HDAC5, EKLF and GATA1 that regulates γ/(γ + β) ratio. We hypothesize that the biological role of this new complex is to shuffle GATA1 and EKLF from the cytoplasm to the nucleus, making them able to engage into the NuRD and Sin3A complex respectively, and that inhibition of the activity of this complex affects γ-globin expression indirectly by limiting the amount of GATA1and EKLF available to associate with NuRD and Sin3A. Disclosures: No relevant conflicts of interest to declare.
5
Migliaccio, Giovanni, Carmela Dell’Aversana, Angela Nebbioso, Elena Alfani, Lilian arricchio, Antonello Mai, Pratima Chaurasia et al. "Ontogenic-Specific Increasesin HDAC1 Activity and Transcription Factor Association During the Maturation of Human Adult Erythroblasts in Vitro." Blood 114, n. 22 (1 novembre 2009): 1978. http://dx.doi.org/10.1182/blood.v114.22.1978.1978.
Testo completoAbstract (sommario):
Abstract Abstract 1978 Poster Board I-1000 Histone deacetylation is one of the major pathways that maintains chromatin in a condensed configuration preventing gene expression in eukaryotic cells. The deacetylation reaction is catalyzed by the histone deacetylase (HDAC) superfamily, which includes eighteen distinct enzymes. HDACs perform their biological function as multiprotein complexes (Sin3A, NuRD and CoREST) that include at least two HDAC isoforms, DNA docking factors (transcription factors and methyl-binding proteins) and protein kinases (PKC). Data from murine cell lines suggest that association of HDAC1 with EKLF and/or Gata1, which occurs as part of the Sin3A or NuRD complex, may provide specificity to the regulation exerted by this enzyme during erythroid maturation. The role of HDAC complexes in primary human erythroid cells has remained poorly defined. The objective of this study was to characterize HDAC expression in human erythroblasts (EB) and monitor changes in expression and activity during maturation in response to erythropoietin (EPO). Human immature EB (iEB) were generated by culturing adult blood (AB) and cord blood (CB) mononuclear cells for 10-12 days with SCF, IL-3, EPO, dexamethasone and estradiol and then for 24-72 hrs in cultures containing EPO alone (mature EB, mEB) (Migliaccio et al, BCMC 28:168, 2002). The levels of HDAC isoform mRNAs and proteins expressed by iEB and mEB, as well as levels of HDAC1 and HDAC5 activity and association of HDAC1 with either GATA1 or EKLF, were then determined. By quantitative RT-PCR, iEB expressed detectable levels of mRNA for all HDAC isoforms, including SIRT 1 and 2. Induction of maturation had modest effects on the level of HDAC mRNA expressed by the EB with the exception of the mRNA for SIRT2 (increased by 10-fold), HDAC2 and HDAC6 (both increased by 2-3-fold). The increase in HDAC6 mRNA observed with maturation correlated with that of GATA1 (HDAC6 is immediately downstream to GATA1). By western-blot analyses, iEB expressed high levels only of HDAC1 to 5 and SIRT1 and 2. Induction of maturation did not affect the HDAC2 and HDAC3 but decreased HDAC1, HDAC4 and HDAC5 and increased SIRT2 protein levels. Therefore, the levels of mRNAs for these genes remained constant but their protein levels decreased with maturation. To evaluate the effect of decrements in protein level on enzymatic activity, the activity of complexes immunoprecipitated with antibodies specific for HDAC1 and HDAC5, the enzymes whose content decreased the most with maturation, from similar numbers of iEB and mEB was compared. iEB expressed HDAC1 and HDAC5 activity levels 2-fold greater than the standard (HeLa extracts). In agreement with the protein levels, HDAC5 activity decreased (by 1-log) with maturation. However, the activity of HDAC1 increased by 2-fold upon EPO exposure. To further characterize the interactions between transcription factors with HDAC1 within the complex, western-blot analyses of proteins co-immunoprecipitated with GATA1 (or HDAC1) from iEB and mEB obtained from CB and AB were compared (see Figure). A greater fraction of GATA 1 was associated with HDAC1 and EKLF in iEB obtained from CB than in those obtained from AB and in both cases the association increased with maturation. In conclusion, these results extend those previously observed with cell lines (Chen and Bieker, Mol Cell Biol 24:10416, 2004) and suggest that erythroid maturation of primary cells is associated with the dynamic regulation of the HDAC1-complex that includes increased enzymatic activity and ontogenetic-specific re-organization of transcription factors recruited to the complex. Disclosures: No relevant conflicts of interest to declare.Disclosures: No relevant conflicts of interest to declare.
6
Hess, Lena, Verena Moos, Arnel A. Lauber, Wolfgang Reiter, Michael Schuster, Natascha Hartl, Daniel Lackner et al. "A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation". PLOS Genetics 18, n. 8 (22 agosto 2022): e1010376. http://dx.doi.org/10.1371/journal.pgen.1010376.
Testo completoAbstract (sommario):
The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimicks class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention.
7
Keedy, Kara S., Nancie M. Archin, Adam T. Gates, Amy Espeseth, Daria J. Hazuda e David M. Margolis. "A Limited Group of Class I Histone Deacetylases Acts To Repress Human Immunodeficiency Virus Type 1 Expression". Journal of Virology 83, n. 10 (11 marzo 2009): 4749–56. http://dx.doi.org/10.1128/jvi.02585-08.
Testo completoAbstract (sommario):
ABSTRACT Silencing of the integrated human immunodeficiency virus type 1 (HIV-1) genome in resting CD4+ T cells is a significant contributor to the persistence of infection, allowing the virus to evade both immune detection and pharmaceutical attack. Nonselective histone deacetylase (HDAC) inhibitors are capable of inducing expression of quiescent HIV-1 in latently infected cells. However, potent global HDAC inhibition can induce host toxicity. To determine the specific HDACs that regulate HIV-1 transcription, we evaluated HDAC1 to HDAC11 RNA expression and protein expression and compartmentalization in the resting CD4+ T cells of HIV-1-positive, aviremic patients. HDAC1, -3, and -7 had the highest mRNA expression levels in these cells. Although all HDACs were detected in resting CD4+ T cells by Western blot analysis, HDAC5, -8, and -11 were primarily sequestered in the cytoplasm. Using chromatin immunoprecipitation assays, we detected HDAC1, -2, and -3 at the HIV-1 promoter in Jurkat J89GFP cells. Targeted inhibition of HDACs by small interfering RNA demonstrated that HDAC2 and HDAC3 contribute to repression of HIV-1 long terminal repeat expression in the HeLa P4/R5 cell line model of latency. Together, these results suggest that HDAC inhibitors specific for a limited number of class I HDACs may offer a targeted approach to the disruption of persistent HIV-1 infection.
8
Masselli, Elena, Lilian Varricchio, Barbara Ghinassi, Carolyn Whitsett, Patricia A. Shi e Anna Rita F. Migliaccio. "Class IIa HDAC Inhibitors Reduce HDAC1 Activity by off-Target Effects Which Reduce GATA1 Expression In Human Erythroblasts Expanded Ex-Vivo". Blood 116, n. 21 (19 novembre 2010): 4780. http://dx.doi.org/10.1182/blood.v116.21.4780.4780.
Testo completoAbstract (sommario):
Abstract Abstract 4780 Histone deacetylation maintains chromatin in a condensed configuration preventing gene expression in eukaryotic cells. The deacetylation reaction is catalyzed by enzymes of the histone deacetylase (HDAC) superfamily, which perform their functions as multiprotein complexes including at least 2 HDAC isoforms, DNA docking factors (transcription factors and methyl-binding proteins) and protein kinases (PKC and Erk). The well established role of HDACs in gene silencing has suggested studies to identify HDAC inhibitors (HDACi) that, by re-activating γ-globin expression, might treat the anemia due to insufficient β-globin expression (Cao et al Blood 103:701, 2004). Over the years several HDACi have been documented to induce γ-globin expression in human erythroid cultures, adult baboons, and β-thalassemia and sickle cell patients. Among those, Class I HDACi, and in particular those that inhibit HDAC3, appear to be more potent as γ-globin gene activators (Mankidy et al, Blood 108:3179, 2006). We have recently identified two new HDACi (compound 9 and 24) which both improved maturation and reactivated γ-globin expression in β°-thalassemic erythroblasts in vitro (Mai et al Mol Pharmacol 72:111, 2007). Compound 24 inhibits both class I (HDAC1 ID50 =0.2 μ M) and class IIa (HDAC4 ID50=0.6 μ M) HDAC. Compound 9 is a class IIa specific inhibitor (HDAC4 ID50=20 μ M) and does not affect HDAC1 activity but is a more potent γ-globin inducer than compound 24. This observation suggests that HDACi may also affect HDAC activity through indirect effects which alter overall complex activity. To clarify possible off-target effects of Class II and Class I/IIa inhibitors and their consequences for erythroid maturation, we analysed expression and activity of different HDAC isoforms during maturation of normal human erythroblasts in vitro at baseline and with treatment with compounds 9 and 24. The proteins studied included GATA1 (the major transcription regulator of erythroid maturation), p21/p27kip1, two cyclin D dependent kinase inhibitors which favor maturation, Caspase 3 (the protease which specifically cleaves GATA1) and Erk (a component of the HDAC complex). During normal erythroid maturation (without HDACi), all the HDAC isoforms were expressed at the mRNA and protein levels. Immunoprecipitation studies followed by determination of HDAC activity indicated that the activities which changed most during maturation are those of HDAC1 (class I), increased by 2-fold, and HDAC5 (class IIa), decreased by 2-fold. In addition, co-immunoprecipitation studies revealed an increase in the association between HDAC1 and GATA1 with erythroid maturation. Changes in the expression of key regulatory proteins were observed with normal erythroid maturation: activation of Caspase 3 decreased with resultant increase in GATA-1, and phosphorylation of pErk decreased while expression of p21 and p27 increased. With exposure to increasing HDACi concentrations (0.2, 2 and 6 μ M), there were class-specific, concentration-dependent alterations in protein expression: compound 9 (Class IIa inhibitor) induced Caspase 3 activation and reduced GATA1 content, while compound 24 decreased Caspase3 activation and greatly increased GATA1 content. In addition, compound 9 did not induce Erk phosphorylation and decreased p21 expression, while compound 24 did induce Erk phosphorylation and inhibited p27 expression (see figure). These results confirm the hypothesis that, in addition to class I inhibitors that directly inhibit class I HDAC, class II HDACi can also affect class I HDAC activity, through indirect effects that involve other components of the complex (repression of GATA1 expression and decrease of Erk phosphorylation). Disclosures: No relevant conflicts of interest to declare.
9
Ibrahim, Hany S., Mohamed Abdelsalam, Yanira Zeyn, Matthes Zessin, Al-Hassan M. Mustafa, Marten A. Fischer, Patrik Zeyen et al. "Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity". International Journal of Molecular Sciences 23, n. 1 (29 dicembre 2021): 369. http://dx.doi.org/10.3390/ijms23010369.
Testo completoAbstract (sommario):
Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.
10
Angiolilli, Chiara, Pawel A. Kabala, Aleksander M. Grabiec, Iris M. Van Baarsen, Bradley S. Ferguson, Samuel García, Beatriz Malvar Fernandez et al. "Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes". Annals of the Rheumatic Diseases 76, n. 1 (25 luglio 2016): 277–85. http://dx.doi.org/10.1136/annrheumdis-2015-209064.
Testo completoAbstract (sommario):
ObjectivesNon-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblast-like synoviocytes (FLS).MethodsRA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)-α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quantitative PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays.ResultsHDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN production and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11.ConclusionsInhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.
11
Ihlefeld, Katja, Ralf Frederik Claas, Alexander Koch, Josef M. Pfeilschifter e Dagmar Meyer zu Heringdorf. "Evidence for a link between histone deacetylation and Ca2+ homoeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts". Biochemical Journal 447, n. 3 (5 ottobre 2012): 457–64. http://dx.doi.org/10.1042/bj20120811.
Testo completoAbstract (sommario):
Embryonic fibroblasts from S1P (sphingosine-1-phosphate) lyase-deficient mice [Sgpl1−/− MEFs (mouse embryonic fibroblasts)] are characterized by intracellular accumulation of S1P, elevated cytosolic [Ca2+]i and enhanced Ca2+ storage. Since S1P, produced by sphingosine kinase 2 in the nucleus of MCF-7 cells, inhibited HDACs (histone deacetylases) [Hait, Allegood, Maceyka, Strub, Harikumar, Singh, Luo, Marmorstein, Kordula, Milstein et al. (2009) Science 325, 1254–1257], in the present study we analysed whether S1P accumulated in the nuclei of S1P lyase-deficient MEFs and caused HDAC inhibition. Interestingly, nuclear concentrations of S1P were disproportionally elevated in Sgpl1−/− MEFs. HDAC activity was reduced, acetylation of histone 3-Lys9 was increased and the HDAC-regulated gene p21 cyclin-dependent kinase inhibitor was up-regulated in these cells. Furthermore, the expression of HDAC1 and HDAC3 was reduced in Sgpl1−/− MEFs. In wild-type MEFs, acetylation of histone 3-Lys9 was increased by the S1P lyase inhibitor 4-deoxypyridoxine. The non-specific HDAC inhibitor trichostatin A elevated basal [Ca2+]i and enhanced Ca2+ storage, whereas the HDAC1/2/3 inhibitor MGCD0103 elevated basal [Ca2+]i without influence on Ca2+ storage in wild-type MEFs. Overexpression of HDAC1 or HDAC2 reduced the elevated basal [Ca2+]i in Sgpl1−/− MEFs. Taken together, S1P lyase-deficiency was associated with elevated nuclear S1P levels, reduced HDAC activity and down-regulation of HDAC isoenzymes. The decreased HDAC activity in turn contributed to the dysregulation of Ca2+ homoeostasis, particularly to the elevated basal [Ca2+]i, in Sgpl1−/− MEFs.
12
Baumann, Philipp, Carmen Junghanns, Strobl Stefan, Fuat Oduncu e Ralf Schmidmaier. "The Novel Pan-HDAC Inhibitor CR2408 Inhibits Multiple Myeloma Cell Growth and Proliferation". Blood 118, n. 21 (18 novembre 2011): 5133. http://dx.doi.org/10.1182/blood.v118.21.5133.5133.
Testo completoAbstract (sommario):
Abstract Abstract 5133 Background: Myeloma (MM) is still an incurable disease, and new cytotoxic drugs are urgently needed. CR2408 is a novel pan-histon deacetylases inhibitor with promising properties and effects in MM cells. Methods: The effect of CR2408 in MM cells was characterized by multiple assays. HDAC inhibition was shown by western blotting as well as HDAC enzyme inhibition assays. Cell growth and viability was shown by the common WST-1 assay. Induction of apoptosis was detected using flow cytometry after annexin-V-FITC staining as well as caspase cleavage detected by western blotting. Basal and cytokine stimulated cell growth rates of myeloma cells were measured by the WST-1 assay. Myeloma cell proliferation was determined by the BrdU assay. Alterations of the cell cycle were determined by flow cytometry after staining with propidium iodide. Modulation of intracellular signalling was shown by western blotting. Results: We have found CR2408 to induce profound hyperacetylation of histone H4 in MM cells. Our experiments revealed that nanomolar concentrations of CR2408 abrogate HDAC activity in 11 HDAC enzymes. Comparison with SAHA shows lower IC50 values for CR2408 (HDAC1 27nM, HDAC2 76nM, HDAC3 28nM, HDAC4 151nM, HDAC5 51nM, HDAC6 13nM, HDAC7 360nM, HDAC8 522nM, HDAC9 92nM, HDAC10 77nM and HDAC11 56nM). CR2408 abrogated myeloma cell growth at nanomolar concentrations (250nM: NCI-H929: −93%; OPM-2: −85%; U266: −87%; RPMI-8226: −86%) and induced apoptosis in multiple myeloma cell lines and primary cells, as shown by the annexin V assay (500nM: NCI-H929: 75%, OPM-2: 65%, RPMI-8226: 80%, U266: 18%, primary cells: 50%). Induction of apoptosis was confirmed by showing cleavage of caspase 3, 8 and 9. Furthermore, increased cell growth induced by conditioned medium obtained from bone marrow stromal cells was abrogated by CR2408. The BrdU assay revealed that inhibition of cell growth was due to inhibition of myeloma cell proliferation (500nM: OPM-2: −50%; RPMI-8226: −58%, U266: −55%). Furthermore, we analysed cell cycle distribution and found that in contrast to other HDAC inhibitors, CD2408 does not provoke a G0/G1 cell cycle arrest but leads to immediate DNA and cell fragmentation, resulting in an accumulation of cell fragments in the subG1 phase. Inhibition of cell proliferation was accompanied by a strong downregulation of the proteins cdc25A, cdk4 and hypophosphorylation of RB. Incubation of myeloma cells with CR2408 did not alter the phosphorylation of 4E-BP-1, P70S6k, but the mitochondrial proteins Bad and Bcl-Xl were downregulated and Bim and pJNK were upregulated. Finally, CR2408 shows significant synergistic effects when combined with doxorubicin and bortezomib. Conclusions: The HDAC inhibitor CR2408 inhibits MM cell proliferation and induces apoptosis. This is accompanied by a strong perturbation of mitochondrial proteins. Since CR2408 inhibit myeloma growth and proliferation as low nanomolar levels, this study provides the rationale for the further in vivo evaluation of CR2408 in order to find a more efficient and less toxic member of this group of compounds. Disclosures: Stefan: 4SC AG: Employment.
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McKinsey, Timothy A., Chun Li Zhang e Eric N. Olson. "Identification of a Signal-Responsive Nuclear Export Sequence in Class II Histone Deacetylases". Molecular and Cellular Biology 21, n. 18 (15 settembre 2001): 6312–21. http://dx.doi.org/10.1128/mcb.21.18.6312-6321.2001.
Testo completoAbstract (sommario):
ABSTRACT Activation of muscle-specific genes by the MEF2 transcription factor is inhibited by class II histone deacetylases (HDACs) 4 and 5, which contain carboxy-terminal deacetylase domains and amino-terminal extensions required for association with MEF2. The inhibitory action of HDACs is overcome by myogenic signals which disrupt MEF2-HDAC interactions and stimulate nuclear export of these transcriptional repressors. Nucleocytoplasmic trafficking of HDAC5 is mediated by binding of the chaperone protein 14-3-3 to two phosphoserine residues (Ser-259 and Ser-498) in its amino-terminal extension. Here we show that HDAC4 and -5 each contain a signal-responsive nuclear export sequence (NES) at their extreme carboxy termini. The NES is conserved in another class II HDAC, HDAC7, but is absent in class I HDACs and the HDAC-related corepressor, MEF2-interacting transcription repressor. Our results suggest that this conserved NES is inactive in unphosphorylated HDAC5, which is localized to the nucleus, and that calcium-calmodulin-dependent protein kinase (CaMK)-dependent binding of 14-3-3 to phosphoserines 259 and 498 activates the NES, with consequent export of the transcriptional repressor to the cytoplasm. A single amino acid substitution in this NES is sufficient to retain HDAC5 in the nucleus in the face of CaMK signaling. These findings provide molecular insight into the mechanism by which extracellular cues alter chromatin structure to promote muscle differentiation and other MEF2-regulated processes.
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Kim, Jwa-Young, Hae-Yong Kweon, Dae-Won Kim, Je-Yong Choi e Seong-Gon Kim. "4-Hexylresorcinol Inhibits Class I Histone Deacetylases in Human Umbilical Cord Endothelial Cells". Applied Sciences 11, n. 8 (13 aprile 2021): 3486. http://dx.doi.org/10.3390/app11083486.
Testo completoAbstract (sommario):
Histone deacetylases (HDACs) are key enzymes for post-translational modification and influence on various cellular activities. Thus, HDACs are associated with many diseases and their inhibitors have clinical significance. Here, 4-Hexylresorcinol (4HR) was studied as an inhibitor for class I HDACs using the HDAC inhibitor (HDACi) Trichostatin-A as a positive control. The 4HR was administered 1–100 μM to human umbilical endothelial cells (HUVECs) and the HDAC expression and activity were examined. The 4HR decreased the expression level of HDAC1, 3, 4, and 5 in a time and dose-dependent manner. The 4HR also increased acetylated lysine and decreased HDAC activity significantly (p < 0.05). Collectively, 4HR was a new class I HDAC inhibitor that reduced the expression and activity of HDAC in HUVECs.
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Xiao, Yufeng, Seth Hale, Nikee Awasthee, Xuan Zhang, Yi Liu, Zhiguang Huo, Dongwen Lyu et al. "Abstract 5347: Selective targeting deacetylase 3 (HDAC3) and HDAC8 by PROTACs". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 5347. http://dx.doi.org/10.1158/1538-7445.am2023-5347.
Testo completoAbstract (sommario):
Abstract Histone deacetylases (HDACs) are enzymes that play an essential role in multiple cellular processes such as DNA transcription, translation, replication, recombination, repair, and metabolism, and their dysregulation can be linked to many different diseases. Most commonly, the overexpression of HDACs is found in various cancer types including hematologic cancers, as well as solid malignancies. Of the many HDACs found in the body, class I HDACs, which consist of HDACs 1, 2, 3, and 8, play an essential role in activating oncogenes underlying tumorigenesis, disease progression, and treatment resistance. Several HDAC inhibitors (HDACis) have been approved for cancer treatment, however, they are pan-inhibitors. This lack of specificity poses many disadvantages for HDACis, including toxicity and other off-target effects. Isozyme-selective inhibitors may reduce these off-target effects and thus enhance their safety. Though favorable, selectivity is difficult to achieve from conventional inhibitors due to the highly homologous catalytic domain among HDAC isozymes. In addition, several HDAC isozymes have deacetylase-independent scaffolding functions that cannot be blocked by traditional inhibitors. Recently, there have been advances in Proteolysis Targeting Chimera (PROTAC), an emerging drug discovery technology designed to hijack cell’s existing protein degradation machinery, the ubiquitin-proteasome system (UPS) to selectively degrade target proteins. Selective degradation by PROTAC is a potential solution to many of the concerns associated with current HDACis. Previously, we reported an HDAC3-selective PROTAC, XZ9002, and following that we reported the discovery of PROTAC YX968, which can degrade both HDAC3 and HDAC8 isozymes with single-digit nanomolar DC50, this highly potent dual degrader exhibits distinct effects on modulating gene expression and is much more potent in inhibiting cancer cell proliferation compared to XZ9002. Based on this, we are further modifying the PROTACs to be selective for HDAC8. The HDAC3, HDAC8 selective degrader and HDAC3 and HDAC8 dual degrader we developed could be useful chemical probes to dissect the complex biological function of HDAC3 and HDAC8 and potential therapeutics for treating cancer. Citation Format: Yufeng Xiao, Seth Hale, Nikee Awasthee, Xuan Zhang, Yi Liu, Zhiguang Huo, Dongwen Lyu, Lei Wang, Weizhou Zhang, Megan Mosteiro, Daiqing Liao, Guangrong Zheng. Selective targeting deacetylase 3 (HDAC3) and HDAC8 by PROTACs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5347.
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Laschanzky, Richard S., Lisa E. Humphrey, Jihyun Ma, Lynette M. Smith, Thomas J. Enke, Surendra K. Shukla, Aneesha Dasgupta et al. "Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy". Cancers 11, n. 9 (7 settembre 2019): 1327. http://dx.doi.org/10.3390/cancers11091327.
Testo completoAbstract (sommario):
Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical efficacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic efficacy. However, their use requires identification of the specific HDACs that mediate the therapeutic effects of HDAC inhibitors in PDAC. We determined that the HDAC1/2/3 inhibitor Mocetinostat synergizes with the HDAC4/5/6 inhibitor LMK-235 in a panel of PDAC cell lines. Furthermore, while neither drug alone synergizes with gemcitabine, the combination of Mocetinostat, LMK-235, and gemcitabine showed strong synergy. Using small interfering (si)RNA-mediated knockdown, this synergy was attributed to inhibition of HDACs 1, 2, and 6. Pharmacological inhibition of HDACs 1 and 2 with Romidepsin and HDAC6 with ACY-1215 also potently synergized with gemcitabine in a panel of PDAC cell lines, and this drug combination potentiated the antitumor effects of gemcitabine against PDAC xenografts in vivo. Collectively, our data show that inhibition of multiple HDACs is required for therapeutic effects of HDAC inhibitors and support the development of novel strategies to inhibit HDACs 1, 2, and 6 for PDAC therapy.
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Grégoire, Serge, Lin Xiao, Jianyun Nie, Xiaohong Zhang, Minghong Xu, Jiarong Li, Jiemin Wong, Edward Seto e Xiang-Jiao Yang. "Histone Deacetylase 3 Interacts with and Deacetylates Myocyte Enhancer Factor 2". Molecular and Cellular Biology 27, n. 4 (11 dicembre 2006): 1280–95. http://dx.doi.org/10.1128/mcb.00882-06.
Testo completoAbstract (sommario):
ABSTRACT The myocyte enhancer factor 2 (MEF2) family of transcription factors is not only important for controlling gene expression in normal cellular programs, like muscle differentiation, T-cell apoptosis, neuronal survival, and synaptic differentiation, but has also been linked to cardiac hypertrophy and other pathological conditions. Lysine acetylation has been shown to modulate MEF2 function, but it is not so clear which deacetylase(s) is involved. We report here that treatment of HEK293 cells with trichostatin A or nicotinamide upregulated MEF2D acetylation, suggesting that different deacetylases catalyze the deacetylation. Related to the trichostatin A sensitivity, histone deacetylase 4 (HDAC4) and HDAC5, two known partners of MEF2, exhibited little deacetylase activity towards MEF2D. In contrast, HDAC3 efficiently deacetylated MEF2D in vitro and in vivo. This was specific, since HDAC1, HDAC2, and HDAC8 failed to do so. While HDAC4, HDAC5, HDAC7, and HDAC9 are known to recognize primarily the MEF2-specific domain, we found that HDAC3 interacts directly with the MADS box. In addition, HDAC3 associated with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation. Furthermore, the nuclear receptor corepressor SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) stimulated the deacetylase activity of HDAC3 towards MEF2 and PCAF. Supporting the physical interaction and deacetylase activity, HDAC3 repressed MEF2-dependent transcription and inhibited myogenesis. These results reveal an unexpected role for HDAC3 and suggest a novel pathway through which MEF2 activity is controlled in vivo.
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Heppt, Markus V., Anja Wessely, Eva Hornig, Claudia Kammerbauer, Saskia A. Graf, Robert Besch, Lars E. French et al. "HDAC2 Is Involved in the Regulation of BRN3A in Melanocytes and Melanoma". International Journal of Molecular Sciences 23, n. 2 (13 gennaio 2022): 849. http://dx.doi.org/10.3390/ijms23020849.
Testo completoAbstract (sommario):
The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal melanocytes or benign nevi. The mechanisms underlying the aberrant expression of BRN3A are unknown. Here, we investigated the epigenetic regulation of BRN3A in melanocytes and melanoma cell lines treated with DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC) inhibitors. DNMT and HAT inhibition did not significantly alter BRN3A expression levels, whereas panHDAC inhibition by trichostatin A led to increased expression. Treatment with the isoform-specific HDAC inhibitor mocetinostat, but not with PCI-34051, also increased BRN3A expression levels, suggesting that class I HDACs HDAC1, HDAC2, and HDAC3, and class IV HDAC11, were involved in the regulation of BRN3A expression. Transient silencing of HDACs 1, 2, 3, and 11 by siRNAs revealed that, specifically, HDAC2 inhibition was able to increase BRN3A expression. ChIP-Seq analysis uncovered that HDAC2 inhibition specifically increased H3K27ac levels at a distal enhancer region of the BRN3A gene. Altogether, our data suggest that HDAC2 is a key epigenetic regulator of BRN3A in melanocytes and melanoma cells. These results highlight the importance of epigenetic mechanisms in regulating melanoma oncogenes.
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Turgeon, Naomie, Julie Moore Gagné, Mylène Blais, Fernand-Pierre Gendron, François Boudreau e Claude Asselin. "The acetylome regulators Hdac1 and Hdac2 differently modulate intestinal epithelial cell dependent homeostatic responses in experimental colitis". American Journal of Physiology-Gastrointestinal and Liver Physiology 306, n. 7 (1 aprile 2014): G594—G605. http://dx.doi.org/10.1152/ajpgi.00393.2013.
Testo completoAbstract (sommario):
Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from dextran sulfate sodium (DSS)-induced murine colitis. Although tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/ Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/ Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/ Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal disease activity index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/ Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability, and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation.
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Guise, Amanda J., Todd M. Greco, Irene Y. Zhang, Fang Yu e Ileana M. Cristea. "Aurora B-dependent Regulation of Class IIa Histone Deacetylases by Mitotic Nuclear Localization Signal Phosphorylation". Molecular & Cellular Proteomics 11, n. 11 (2 agosto 2012): 1220–29. http://dx.doi.org/10.1074/mcp.m112.021030.
Testo completoAbstract (sommario):
Class IIa histone deacetylases (HDACs 4/5/7/9) are transcriptional regulators with critical roles in cardiac disease and cancer. HDAC inhibitors are promising anticancer agents, and although they are known to disrupt mitotic progression, the underlying mechanisms of mitotic regulation by HDACs are not fully understood. Here we provide the first identification of histone deacetylases as substrates of Aurora B kinase (AurB). Our study identifies class IIa HDACs as a novel family of AurB targets and provides the first evidence that HDACs are temporally and spatially regulated by phosphorylation during the cell cycle. We define the precise site of AurB-mediated phosphorylation as a conserved serine within the nuclear localization signals of HDAC4, HDAC5, and HDAC9 at Ser265, Ser278, and Ser242, respectively. We establish that AurB interacts with these HDACs in vivo, and that this association increases upon disruption of 14-3-3 binding. We observe colocalization of endogenous, phosphorylated HDACs with AurB at the mitotic midzone in late anaphase and the midbody during cytokinesis, complemented by a reduction in HDAC interactions with components of the nuclear corepressor complex. We propose that AurB-dependent phosphorylation of HDACs induces sequestration within a phosphorylation gradient at the midzone, maintaining separation from re-forming nuclei and contributing to transcriptional control.
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Han, Ying, Le Chen, Jingyun Liu, Jie Chen, Chunyang Wang, Yu Guo, Xuebin Yu, Chenghong Zhang, Haiying Chu e Haiying Ma. "A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway". Molecules 27, n. 13 (29 giugno 2022): 4160. http://dx.doi.org/10.3390/molecules27134160.
Testo completoAbstract (sommario):
As a neurodegenerative disease, Alzheimer’s disease (AD) seriously affects the health of older people. Changes in synapses occur first over the course of the disease, perhaps even before the formation of Aβ plaques. Histone deacetylase (HDAC) mediates the damage of Aβ oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects using an HDAC inhibitor (HDACI), BG45, in the human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APP/PS1 transgenic mice during this study. The cells were treated with 15 μM BG45 and the APP/PS1 mice were treated with 30 mg/kg BG45. We detected the levels of synapse-related proteins, HDACs, tau phosphorylation, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors using Western blotting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA levels of the glutamate ion receptor alginate subunit 2 (GRIK2), sodium voltage-gated channel beta subunit (SCN3B), synaptophysin (SYP), Grm2 (the gene encoding glutamate receptor subunit 2 (GluR2)), Grid2IP, glutamate receptor interacting protein 1 (GRIP1), and GRIP2 were detected to explore the effects of the HDACI on regulating the expression of synaptic proteins and AMPA receptors. According to our studies, the expressions of HDAC1, HDAC2, and HDAC3 were increased, which were accompanied by the downregulation of the synapse-related proteins SYP, postsynaptic dendritic protein (PSD-95), and spinophilin as early as 24 h after transfection with the APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptosis-mediated loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aβ deposition and phosphorylation of tau, and increased the levels of the synapse-related genes GRIK2, SCN3B, SYP, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2, and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. Based on these results, HDACs are involved in the early process of synaptic defects in AD models, and BG45 may rescue synaptic damage and the loss of hippocampal neurons by specifically inhibiting HDAC1, HDAC2, and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression, and finally enhancing the function of excitatory synapses. BG45 may be considered a potential drug for the treatment of early AD in further studies.
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Kraft, Fabian B., Maria Hanl, Felix Feller, Linda Schäker-Hübner e Finn K. Hansen. "Photocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer Therapy". Pharmaceuticals 16, n. 3 (25 febbraio 2023): 356. http://dx.doi.org/10.3390/ph16030356.
Testo completoAbstract (sommario):
Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide range of adverse effects. One approach to avoiding off-target effects is the use of prodrugs enabling a controlled release of the inhibitor in the target tissue. Herein, we describe the synthesis and biological evaluation of HDACi prodrugs with photo-cleavable protecting groups masking the zinc-binding group of the established HDACi DDK137 (I) and VK1 (II). Initial decaging experiments confirmed that the photocaged HDACi pc-I could be deprotected to its parent inhibitor I. In HDAC inhibition assays, pc-I displayed only low inhibitory activity against HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of pc-I strongly increased. Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis confirmed the inactivity of pc-I at the cellular level. Upon irradiation, pc-I demonstrated pronounced HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor I. Additionally, only phototreated pc-I was able to induce apoptosis in Annexin V/PI and caspase-Glo 3/7 assays, making pc-I a valuable tool for the development of light-activatable HDACi.
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Lewis, A., B. Pan-Castillo, G. Berti, C. Felice, H. Gordon, R. Gadhok, A. Minicozzi et al. "DOP23 Single-cell RNA sequencing identifies an important role for class I histone-deacetylase enzymes in intestinal myofibroblasts from patients with Crohn’s Disease strictures". Journal of Crohn's and Colitis 15, Supplement_1 (1 maggio 2021): S062. http://dx.doi.org/10.1093/ecco-jcc/jjab073.062.
Testo completoAbstract (sommario):
Abstract Background Histone-deacetylase (HDAC) enzymes are a broad class of ubiquitously expressed enzymes that modulate histone acetylation, chromatin accessibility and gene expression. In models of Inflammatory bowel disease (IBD), HDAC inhibitors, such as Valproic acid (VPA) are proven anti-inflammatory agents and evidence suggests that they also inhibit fibrosis in non-intestinal organs. However, the role of HDAC enzymes in stricturing Crohn’s disease (CD) has not been characterised; this is key to understanding the molecular mechanism and developing novel therapies. Methods To evaluate HDAC expression in the intestine of SCD patients, we performed unbiased single-cell RNA sequencing (sc-RNA-seq) of over 10,000 cells isolated from full-thickness surgical resection specimens of non-SCD (NSCD; n=2) and SCD intestine (n=3). Approximately, 1000 fibroblasts were identified for further analysis, including a distinct cluster of myofibroblasts. Changes in gene expression were compared between myofibroblasts and other resident intestinal fibroblasts using the sc-RNA-seq analysis pipeline in Partek. Changes in HDAC expression and markers of HDAC activity (H3K27ac) were confirmed by immunohistochemistry in FFPE tissue from patient matched NSCD and SCD intestine (n=14 pairs). The function of HDACs in intestinal fibroblasts in the CCD-18co cell line and primary CD myofibroblast cultures (n=16 cultures) was assessed using VPA, a class I HDAC inhibitor. Cells were analysed using a variety of molecular techniques including ATAC-seq, gene expression arrays, qPCR, western blot and immunofluorescent protein analysis. Results Class I HDAC (HDAC1, p= 2.11E-11; HDAC2, p= 4.28E-11; HDAC3, p= 1.60E-07; and HDAC8, p= 2.67E-03) expression was increased in myofibroblasts compared to other intestinal fibroblasts subtypes. IHC also showed an increase in the percentage of stromal HDAC2 positive cells, coupled with a decrease in the percentage of H3K27ac positive cells, in the mucosa overlying SCD intestine relative to matched NSCD areas. In the CCD-18co cell line and primary myofibroblast cultures, VPA reduced chromatin accessibility at Collagen-I gene promoters and suppressed their transcription. VPA also inhibited TGFB-induced up-regulation of Collagen-I, in part by inhibiting TGFB1|1/SMAD4 signalling. TGFB1|1 was identified as a mesenchymal specific target of VPA and siRNA knockdown of TGFB1|1 was sufficient suppress TGFB-induced up-regulation of Collagen-I. Conclusion In SCD patients, class I HDAC expression is increased in myofibroblasts. Class I HDACs inhibitors impair TGFB-signalling and inhibit Collagen-I expression. Selective targeting of TGFB1|1 offers the opportunity to increase treatment specificity by selectively targeting meschenymal cells.
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Ariffin, Juliana K., Kaustav das Gupta, Ronan Kapetanovic, Abishek Iyer, Robert C. Reid, David P. Fairlie e Matthew J. Sweet. "Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages". Antimicrobial Agents and Chemotherapy 60, n. 3 (28 dicembre 2015): 1521–29. http://dx.doi.org/10.1128/aac.01876-15.
Testo completoAbstract (sommario):
Broad-spectrum histone deacetylase inhibitors (HDACi) are used clinically as anticancer agents, and more isoform-selective HDACi have been sought to modulate other conditions, including chronic inflammatory diseases. Mouse studies suggest that HDACi downregulate immune responses and may compromise host defense. However, their effects on human macrophage antimicrobial responses are largely unknown. Here, we show that overnight pretreatment of human macrophages with HDACi prior to challenge withSalmonella entericaserovar Typhimurium orEscherichia coliresults in significantly reduced intramacrophage bacterial loads, which likely reflect the fact that this treatment regime impairs phagocytosis. In contrast, cotreatment of human macrophages with HDACi at the time of bacterial challenge did not impair phagocytosis; instead, HDACi cotreatment actually promoted clearance of intracellularS. Typhimurium andE. coli. Mechanistically, treatment of human macrophages with HDACi at the time of bacterial infection enhanced mitochondrial reactive oxygen species generation by these cells. The capacity of HDACi to promote the clearance of intracellular bacteria from human macrophages was abrogated when cells were pretreated with MitoTracker Red CMXRos, which perturbs mitochondrial function. The HDAC6-selective inhibitor tubastatin A promoted bacterial clearance from human macrophages, whereas the class I HDAC inhibitor MS-275, which inhibits HDAC1 to -3, had no effect on intracellular bacterial loads. These data are consistent with HDAC6 and/or related HDACs constraining mitochondrial reactive oxygen species production from human macrophages during bacterial challenge. Our findings suggest that, whereas long-term HDACi treatment regimes may potentially compromise host defense, selective HDAC inhibitors may have applications in treating acute bacterial infections.
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Guenther, Matthew G., Orr Barak e Mitchell A. Lazar. "The SMRT and N-CoR Corepressors Are Activating Cofactors for Histone Deacetylase 3". Molecular and Cellular Biology 21, n. 18 (15 settembre 2001): 6091–101. http://dx.doi.org/10.1128/mcb.21.18.6091-6101.2001.
Testo completoAbstract (sommario):
ABSTRACT Repression of gene transcription is linked to regulation of chromatin structure through deacetylation of core histone amino-terminal tails. This action is mediated by histone deacetylases (HDACs) that function within active multiprotein complexes directed to the promoters of repressed genes. In vivo, HDAC3 forms a stable complex with the SMRT corepressor. The SMRT-HDAC3 complex exhibits histone deacetylase activity, whereas recombinant HDAC3 is an inactive enzyme. Here we report that SMRT functions as an activating cofactor of HDAC3. In contrast, SMRT does not activate the class II HDAC4, with which it also interacts. Activation of HDAC3 is mediated by a deacetylase activating domain (DAD) that includes one of two SANT motifs present in SMRT. A cognate DAD is present in the related corepressor N-CoR, which can also activate HDAC3. Mutations in the DAD that abolish HDAC3 interaction also eliminate reconstitution of HDAC activity. Using purified components, the SMRT DAD is shown to be necessary and sufficient for activation of HDAC3. Moreover, the DAD is required both for HDAC3 to function enzymatically and for the major repression function of SMRT. Thus, SMRT and N-CoR do not serve merely as platforms for HDAC recruitment but function as an integral component of an active cellular HDAC3 enzyme.
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Cao, Biyin, Mingyun Shen, Depei Wu, Jianhong Du, Jingyu Zhu, Suning Chen, Aining Sun et al. "The Proteasomal Inhibitor Clioquinol Induces Apoptosis in Leukemia and Myeloma Cells by Inhibiting Histone Deacetylase Activity." Blood 120, n. 21 (16 novembre 2012): 2449. http://dx.doi.org/10.1182/blood.v120.21.2449.2449.
Testo completoAbstract (sommario):
Abstract Abstract 2449 Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline, CQ) is an anti-fungal and anti-parasitic drug and is also a strong chelator of divalent metal ions such as zinc, and copper. Recent studies suggested by formation a metal complex, CQ becomes an inhibitor of proteasomes and displays anti-cancer activity in several types of solid cancers including prostate cancers and breast cancers. Although addition of copper and other divalent mental ions increases the activity of CQ in terms of proteasomal inhibition and cell death, our recent studies found that CQ and its analog 5-amino-8-hydroquinoline display potent anti-leukemia and anti-myeloma activity without addition of such metal ions. Because CQ is a potent chelator of zinc that is indispensable for many biological enzymes, such as histone deacetylases (HDACs). HDACs are a class of zinc-dependent enzymes regulating gene expression, cell survival and cell death. We questioned that whether CQ induces apoptosis by inhibiting HDAC activity via interfering with zinc in the active sites of these enzymes. To answer this question, we first analyzed the effects of clioquinol on transcription of HDAC-regulated genes including p21, p27 and p53. After 24 hr treatment, expression of these genes was significantly increased by CQ in a concentration-dependent manner. Consistent with these findings, CQ also induced cell cycle arrest and cell apoptosis, a sign of HDAC inhibition. We then examined HDAC activity by evaluating the expression level of acetylated histone 3 (Ac-H3). As expected, Ac-H3 was increased by CQ in all examined cell lines and bone marrow cells from primary leukemia and myeloma patients. CQ also induced accumulation of acetylated p53 and acetylated HSP90. In the mechanistic study, we further surveyed the effects of CQ on a panel of HDACs, including HDAC-1, −2, −3, −5 and −8, and found that most enzymes but HDAC2 were decreased by CQ at concentrations of 20 mM or higher in both myeloma and leukemia cells. Since CQ increased Ac-H3 at a concentration as low as 5 mM, we wondered whether CQ binds to HDACs thus directly interfering with their activity. To this end, we next screened the effects of CQ on all 11 zinc-dependent HDACs, including Class I (HDAC1, 2, 3, 8), Class 2A (HDAC4, -5, -7, -9) and Class 2B (HDAC6, -10) and Class IV (HDAC11) and measured the values of IC50 to each enzyme. The results showed that CQ had no effects on activities of Class 2B (HDAC6-, -10) and Class IV (HDAC11). Compared with trichostatin, the classic HDAC inhibitor, CQ displayed similar inhibition to Class 2A HDACs, but the IC50 values to Class I HDACs were 1000 fold higher than trichostatin. Thus, CQ probably mainly targeted Class 2A HDACs. To demonstrate this hypothesis, we analyzed the interaction between CQ and HDAC by computer modeling. The result indicated that CQ was well docked into the active pocket of the enzyme, where the oxygen and nitrogen atoms in CQ formed stable coordinate bonds with the zinc ion, and the hydroxyl group from CQ formed an effective hydrogen bond with Asp267. Moreover, CQ formed extensive van der Waals interactions with hydrophobic residues Trp141, Phe152 and Try306. To further verify this prediction, we co-treated cells with CQ and zinc chloride, and found that CQ-induced accumulation of Ac-H3 was attenuated by zinc. Thus, the proteasomal inhibitor CQ can induce apoptosis in leukemia and myeloma by inhibiting the HDAC activity, especially Class 2A enzymes. This study proposed a new line of mechanism for understanding CQ in the treatment of leukemia and myeloma. Disclosures: No relevant conflicts of interest to declare.
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Kim, Min Young, Bowen Yan, Suming Huang e Yi Qiu. "Regulating the Regulators: The Role of Histone Deacetylase 1 (HDAC1) in Erythropoiesis". International Journal of Molecular Sciences 21, n. 22 (11 novembre 2020): 8460. http://dx.doi.org/10.3390/ijms21228460.
Testo completoAbstract (sommario):
Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. Class I deacetylase HDAC1/2 often associates with repressor complexes, such as Sin3 (Switch Independent 3), NuRD (Nucleosome remodeling and deacetylase) and CoREST (Corepressor of RE1 silencing transcription factor) complexes. It has been shown that HDAC1 interacts with and modulates all essential transcription factors for erythropoiesis. During erythropoiesis, histone deacetylase activity is dramatically reduced. Consistently, inhibition of HDAC activity promotes erythroid differentiation. The reduction of HDAC activity not only results in the activation of transcription activators such as GATA-1 (GATA-binding factor 1), TAL1 (TAL BHLH Transcription Factor 1) and KLF1 (Krüpple-like factor 1), but also represses transcription repressors such as PU.1 (Putative oncogene Spi-1). The reduction of histone deacetylase activity is mainly through HDAC1 acetylation that attenuates HDAC1 activity and trans-repress HDAC2 activity through dimerization with HDAC1. Therefore, the acetylation of HDAC1 can convert the corepressor complex to an activator complex for gene activation. HDAC1 also can deacetylate non-histone proteins that play a role on erythropoiesis, therefore adds another layer of gene regulation through HDAC1. Clinically, it has been shown HDACi can reactivate fetal globin in adult erythroid cells. This review will cover the up to date research on the role of HDAC1 in modulating key transcription factors for erythropoiesis and its clinical relevance.
28
Tang, Jinhua, Yanli Yan, Ting C. Zhao, George Bayliss, Haidong Yan e Shougang Zhuang. "Class I histone deacetylase activity is required for proliferation of renal epithelial cells". American Journal of Physiology-Renal Physiology 305, n. 3 (1 agosto 2013): F244—F254. http://dx.doi.org/10.1152/ajprenal.00126.2013.
Testo completoAbstract (sommario):
The process of renal regeneration after acute kidney injury is thought to recapitulate renal development, and proliferation of renal proximal tubular cells (RPTCs) is a critical step in the regenerative response. Recent studies indicate that class I histone deacetylases (HDACs) are required for embryonic kidney gene expression, growth, and differentiation. The role and underlying mechanisms of class I HDAC activation in RPTC proliferation, however, remain unclear. In this study, we used cultured RPTCs to examine this issue since four class I HDAC isoforms (1, 2, 3, and 8) are abundantly expressed in this cell type. Blocking class I HDAC activity with a highly selective inhibitor, MS-275, induced global histone H3 hyperacetylation, reduced RPTC proliferation, and diminished expression of cyclin D1 and proliferating cell nuclear antigen. Silencing HDAC1, 3, or 8 with small interfering RNA resulted in similar biological effects. Activation of epidermal growth factor receptor (EGFR) and signal transducers and activators of transcription 3 (STAT3) was required for RPTC proliferation, and STAT3 functioned downstream of EGFR. Treatment with MS-275 or knockdown of HDAC1, 3, or 8 suppressed EGFR expression and phosphorylation, and silencing HDAC1 and 3 also reduced STAT3 phosphorylation. However, HDAC2 downregulation did not affect RPTC proliferation and phosphorylation of EGFR and STAT3. Collectively, these data reveal a critical role of class I HDACs in mediating proliferation of renal epithelial cells through activation of the EGFR/STAT3 signaling pathway.
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Moreth, Kristin, Daniel Riester, Christian Hildmann, René Hempel, Dennis Wegener, Andreas Schober e Andreas Schwienhorst. "An active site tyrosine residue is essential for amidohydrolase but not for esterase activity of a class 2 histone deacetylase-like bacterial enzyme". Biochemical Journal 401, n. 3 (12 gennaio 2007): 659–65. http://dx.doi.org/10.1042/bj20061239.
Testo completoAbstract (sommario):
HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells acting through deacetylation of ϵ-acetyl-lysine residues within the N-terminal tail of core histones. In addition, both eukaryotic HDACs as well as their bacterial counterparts were reported to also act on non-histone targets. However, we are still far from a comprehensive understanding of the biological activities of this ancient class of enzymes. In the present paper, we studied in more detail the esterase activity of HDACs, focussing on the HDAH (histone deacetylase-like amidohydrolase) from Bordetella/Alcaligenes strain FB188. This enzyme was classified as a class 2 HDAC based on sequence comparison as well as functional data. Using chromogenic and fluorogenic ester substrates we show that HDACs such as FB188 HDAH indeed have esterase activity that is comparable with those of known esterases. Similar results were obtained for human HDAC1, 3 and 8. Standard HDAC inhibitors were able to block both activities with similar IC50 values. Interestingly, HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA) also showed inhibitory activity against porcine liver esterase and Pseudomonas fluorescens lipase. The esterase and the amidohydrolase activity of FB188 HDAH both appear to have the same substrate specificity concerning the acyl moiety. Interestingly, a Y312F mutation in the active site of HDAH obstructed amidohydrolase activity but significantly improved esterase activity, indicating subtle differences in the mechanism of both catalytic activities. Our results suggest that, in principle, HDACs may have other biological roles besides acting as protein deacetylases. Furthermore, data on HDAC inhibitors affecting known esterases indicate that these molecules, which are currently among the most promising drug candidates in cancer therapy, may have a broader target profile requiring further exploration.
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Hamoud, Mohamed M. S., Sravani Pulya, Nermine A. Osman, Yamini Bobde, Abdalla E. A. Hassan, Hanan A. Abdel-Fattah, Balaram Ghosh e Amany M. Ghanim. "Design, synthesis, and biological evaluation of novel nicotinamide derivatives as potential histone deacetylase-3 inhibitors". New Journal of Chemistry 44, n. 23 (2020): 9671–83. http://dx.doi.org/10.1039/d0nj01274b.
Testo completo
31
Weiss, Ulrike, Moritz Möller, Sayed Adham Husseini, Christine Manderscheid, Julia Häusler, Gerd Geisslinger e Ellen Niederberger. "Inhibition of HDAC Enzymes Contributes to Differential Expression of Pro-Inflammatory Proteins in the TLR-4 Signaling Cascade". International Journal of Molecular Sciences 21, n. 23 (25 novembre 2020): 8943. http://dx.doi.org/10.3390/ijms21238943.
Testo completoAbstract (sommario):
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.
32
Ding, Jianming (Diane), Masaki Ri, Tomoko Narita, Ayako Masaki, Fumiko Mori, Asahi Ito, Shigeru Kusumoto et al. "Reduced Expression of HDAC3 Contributes to the Resistance Against HDAC Inhibitor, Vorinostat (SAHA) in Mature Lymphoid Malignancies". Blood 120, n. 21 (16 novembre 2012): 1342. http://dx.doi.org/10.1182/blood.v120.21.1342.1342.
Testo completoAbstract (sommario):
Abstract Abstract 1342 In mature lymphoid malignancies including T-cell lymphoma and multiple myeloma (MM), aberrant acetylation status has been strongly linked to their tumorigenesis. Thus, the modulation of acetylation through targeting histone deacetylases (HDACs) is considered to be a viable therapeutic strategy. Vorinostat (SAHA) is the first HDAC inhibitor approved by the FDA for the patients with cutaneous T-cell lymphoma (CTCL). Anti-tumor activity of SAHA against CTCL, adult T-cell leukemia/lymphoma (ATLL), and MM cell lines was examined. Most of these cells were found to be sensitive to this drug at IC50 of less than 1–2uM. For further clarification of its mechanism of action, we established five SAHA-resistant cell lines consisting of 3 CTCL and 2 MM using dose stepwise increase method over six months. IC50 of the SAHA-resistant cells was 4-to 14-fold higher than that of their parental cells. These cell lines also showed cross-resistance of 2.8- to 17.5-fold against another pan-HDAC inhibitor, panobinostat (LBH589). Regarding HDAC activity, it was greatly inhibited by SAHA in parental cells, whereas it was only partly inhibited in SAHA-resistant cells. That is, SAHA-resistant cells have lost apart of the HDAC inhibiting function caused by SAHA. Moreover, SAHA-resistant cells showed higher anti-apoptosis ability when exposed with SAHA than their parental cells with acetylation status of histone H3 being remained low. Next, we performed microarray analysis to compare expression levels of various HDACs and other related genes between parental and SAHA-resistant cells. Results indicated that the expression level of HDAC3 being obviously low in resistant cells among various HDACs, which was also confirmed by real-time PCR. In line with mRNA analysis, protein level of HDAC3 was also decreased in SAHA-resistant cells compared with their parental cells, while other HDAC expression remained unchanged. We assumed that HDAC3 could be a main target of SAHA. To examine this possibility, we established both HDAC3 knocked-down and over-expressing cell lines, and examined the sensitivity of these cells to SAHA. HDAC3 knocked-down cells showed obviously SAHA-resistant feature in MTS assay, however, HDAC3 over-expressing cells showed higher sensitivity to SAHA. Knocking out other HDACs (1, 2 and 8) in parental cell lines did not change the sensitivity to SAHA. Thus, our results suggest that SAHA induced apoptosis depends on the inhibition of HDAC3. To search for other possible mechanisms, we screened for the mutations in HDAC2, 3, 4 and 8, but did not find them. Finally, we supposed that HDAC3 expression was epigenetically silenced by promoter methylation in SAHA resistant cells, and attempted to restore HDAC3 expression in the presence of 5-azacytidine, a DNA demethylase. We incubated SAHA-resistant cells with non-toxic levels of 5-azacytidine (4uM) for 9 days, and confirmed that HDAC3 expression was restored during 6–9 days after exposure. When HDAC3 expression being restored, the resistant cells showed higher sensitivity to SAHA. It suggests that hyper-methylation of promoter sequences of HDAC3 contributed to the mechanism of SAHA-resistance. From these results, we conclude that anti-tumor effect of HDAC inhibitors depends on the expression level of HDCA3 in mature lymphoid malignancies, and HDAC3 might provide a useful biomarker for identifying favorable response to HDAC inhibitors, and the overcoming the resistance of HDAC inhibitors. Disclosures: No relevant conflicts of interest to declare.
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Di Giorgio, Eros, Andrea Clocchiatti, Sara Piccinin, Andrea Sgorbissa, Giulia Viviani, Paolo Peruzzo, Salvatore Romeo et al. "MEF2 Is a Converging Hub for Histone Deacetylase 4 and Phosphatidylinositol 3-Kinase/Akt-Induced Transformation". Molecular and Cellular Biology 33, n. 22 (16 settembre 2013): 4473–91. http://dx.doi.org/10.1128/mcb.01050-13.
Testo completoAbstract (sommario):
The MEF2-class IIa histone deacetylase (HDAC) axis operates in several differentiation pathways and in numerous adaptive responses. We show here that nuclear active HDAC4 and HDAC7 display transforming capability. HDAC4 oncogenic potential depends on the repression of a limited set of genes, most of which are MEF2 targets. Genes verified as targets of the MEF2-HDAC axis are also under the influence of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway that affects MEF2 protein stability. A signature of MEF2 target genes identified by this study is recurrently repressed in soft tissue sarcomas. Correlation studies depicted two distinct groups of soft tissue sarcomas: one in which MEF2 repression correlates with PTEN downregulation and a second group in which MEF2 repression correlates with HDAC4 levels. Finally, simultaneous pharmacological inhibition of the PI3K/Akt pathway and of MEF2-HDAC interaction shows additive effects on the transcription of MEF2 target genes and on sarcoma cells proliferation. Overall, our work pinpoints an important role of the MEF2-HDAC class IIa axis in tumorigenesis.
34
Elbatrawy, Omnia R., Mohamed Hagras, Moshira A. El Deeb, Fatimah Agili, Maghawry Hegazy, Ahmed A. El-Husseiny, Mahmoud Mohamed Mokhtar, Samy Y. Elkhawaga, Ibrahim H. Eissa e Samar El-Kalyoubi. "Discovery of New Uracil and Thiouracil Derivatives as Potential HDAC Inhibitors". Pharmaceuticals 16, n. 7 (6 luglio 2023): 966. http://dx.doi.org/10.3390/ph16070966.
Testo completoAbstract (sommario):
Background: Histone deacetylase inhibitors (HDACIs) are a relatively new class of potential drugs for treating cancer. Aim: Discovery of new anticancer agents targeting HDAC. Methods: New uracil and thiouracil derivatives panels were designed and synthesized as HDAC inhibitors. The synthesized compounds were tested against MCF-7, HepG2, and HCT-116. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. The most active member was tested for its potential against cell cycle, apoptosis, caspase-3, and caspase-8. Docking studies were carried out against HDAC1. Results: Compounds 5a, 5b, 5f, 5i, 5k, and 5m exhibited promising cytotoxic activities. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. Regarding the HDAC1 inhibitory activity, compound 5m was the most potent member (IC50 = 0.05 µg/mL) compared to trichostatin A (IC50 = 0.0349 µg/mL). For HDAC4, compound 5m showed superior activity (IC50 = 2.83 µg/mL) than trichostatin A (IC50 = 3.349 µg/mL). Compound 5m showed a high potential to arrest the HCT116 cell cycle at the G0-G1 phase. In addition, it showed an almost 17 times apoptotic effect (37.59%) compared to the control cells (2.17%). Furthermore, Compound 5m showed significant increases in the levels of caspase-3 and caspase-8. Finally, the uracil and thiouracil derivatives showed accepted binding mods against HDAC. Conclusions: Compound 5m has potential anticancer activity targeting HDAC with a significant apoptotic effect.
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Luo, Yuxiang, e Huilin Li. "Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)". International Journal of Molecular Sciences 21, n. 22 (22 novembre 2020): 8828. http://dx.doi.org/10.3390/ijms21228828.
Testo completoAbstract (sommario):
Class I histone deacetylases (HDACs) are promising targets for epigenetic therapies for a range of diseases such as cancers, inflammations, infections and neurological diseases. Although six HDAC inhibitors are now licensed for clinical treatments, they are all pan-inhibitors with little or no HDAC isoform selectivity, exhibiting undesirable side effects. A major issue with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Except for HDAC8, Class I HDACs (1, 2 and 3) are recruited to large multiprotein complexes to function. Therefore, there are rising needs to develop new, hopefully, therapeutically efficacious HDAC inhibitors with isoform or complex selectivity. Here, upon the introduction of the structures of Class I HDACs and their complexes, we provide an up-to-date overview of the structure-based discovery of Class I HDAC inhibitors, including pan-, isoform-selective and complex-specific inhibitors, aiming to provide an insight into the discovery of additional HDAC inhibitors with greater selectivity, specificity and therapeutic utility.
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Rizzotto, Lara, Arianna Bottoni, Tzung-Huei Lai, Chaomei Liu, Pearlly S. Yan, Hatice G. Ozer, Rosa Lapalombella et al. "Role of Histone Deacetylase-Mediated Gene Silencing in Chronic Lymphocytic Leukemia Progression". Blood 128, n. 22 (2 dicembre 2016): 2705. http://dx.doi.org/10.1182/blood.v128.22.2705.2705.
Testo completoAbstract (sommario):
Abstract Chronic lymphocytic leukemia (CLL) follows a variable clinical course mostly dependent upon genomic factors, with a subset of patients having low risk disease and others displaying rapid progression associated with clonal evolution. Epigenetic mechanisms such as DNA promoter hypermethylation were shown to have a role in CLL evolution where the acquisition of increasingly heterogeneous DNA methylation patters occurred in conjunction with clonal evolution of genetic aberrations and was associated with disease progression. However the role of epigenetic mechanisms regulated by the histone deacetylase group of transcriptional repressors in the progression of CLL has not been well characterized. The histone deacetylases (HDACs) 1 and 2 are recruited onto gene promoters and form a complex with the histone demethylase KDM1. Once recruited, the complex mediate the removal of acetyl groups from specific lysines on histones (H3K9 and H3K14) thus triggering the demethylation of lysine 4 (H3K4me3) and the silencing of gene expression. CLL is characterized by the dysregulation of numerous coding and non coding genes, many of which have key roles in regulating the survival or progression of CLL. For instance, our group showed that the levels of HDAC1 were elevated in high risk as compared to low risk CLL or normal lymphocytes and this over-expression was responsible for the silencing of miR-106b, mR-15, miR-16, and miR-29b which affected CLL survival by modulating the expression of key anti-apoptotic proteins Bcl-2 and Mcl-1. To characterize the HDAC-repressed gene signature in high risk CLL, we conducted chromatin immunoprecipitation (ChIP) of the nuclear lysates from 3 high risk and 3 low risk CLL patients using antibodies against HDAC1, HDAC2 and KDM1 or non-specific IgG, sequenced and aligned the eluted DNA to a reference genome and determined the binding of HDAC1, HDAC2 and KDM1 at the promoters for all protein coding and microRNA genes. Preliminary results from this ChIP-seq showed a strong recruitment of HDAC1, HDAC2 and KDM1 to the promoters of several microRNA as well as protein coding genes in high risk CLL. To further corroborate these data we performed ChIP-Seq in the same 6 CLL samples to analyze the levels of H3K4me2 and H3K4me3 around gene promoters before and after 6h exposure to the HDACi panobinostat. Our goal was to demonstrate that HDAC inhibition elicited an increase in the levels of acetylation on histones and triggered the accrual of H3K4me2 at the repressed promoter, events likely to facilitate the recruitment of RNA polymerase II to this promoter. Initial analysis confirmed a robust accumulation of H3K4me2 and H3K4me3 marks at the gene promoters of representative genes that recruited HDAC1 and its co-repressors in the previous ChIP-Seq analysis in high risk CLL patients. Finally, 5 aggressive CLL samples were treated with the HDACi abexinostat for 48h and RNA before and after treatment was subjected to RNA-seq for small and large RNA to confirm that the regions of chromatin uncoiled by HDACi treatment were actively transcribed. HDAC inhibition induced the expression of a large number of miRNA genes as well as key protein coding genes, such as miR-29b, miR-210, miR-182, miR-183, miR-95, miR-940, FOXO3, EBF1 and BCL2L11. Of note, some of the predicted or validated targets of the induced miRNAs were key facilitators in the progression of CLL, such as BTK, SYK, MCL-1, BCL-2, TCL1, and ROR1. Moreover, RNA-seq showed that the expression of these protein coding genes was reduced by 2-33 folds upon HDAC inhibition. We plan to extend the RNA-seq to 5 CLL samples with indolent disease and combine all the data to identify a common signature of protein coding and miRNA genes that recruited the HDAC1 complex, accumulated activating histone modifications upon treatment with HDACi and altered gene and miRNA expression after HDAC inhibition in high risk CLL versus low risk CLL. The signature will be than validated on a large cohort of indolent and aggressive CLL patients. Our final goal is to define a signature of coding and non coding genes silenced by HDACs in high risk CLL and its role in facilitating disease progression. Disclosures Woyach: Acerta: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding.
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Gomis-Coloma, Clara, Sergio Velasco-Aviles, Jose A. Gomez-Sanchez, Angeles Casillas-Bajo, Johannes Backs e Hugo Cabedo. "Class IIa histone deacetylases link cAMP signaling to the myelin transcriptional program of Schwann cells". Journal of Cell Biology 217, n. 4 (22 febbraio 2018): 1249–68. http://dx.doi.org/10.1083/jcb.201611150.
Testo completoAbstract (sommario):
Schwann cells respond to cyclic adenosine monophosphate (cAMP) halting proliferation and expressing myelin proteins. Here we show that cAMP signaling induces the nuclear shuttling of the class IIa histone deacetylase (HDAC)–4 in these cells, where it binds to the promoter and blocks the expression of c-Jun, a negative regulator of myelination. To do it, HDAC4 does not interfere with the transcriptional activity of MEF2. Instead, by interacting with NCoR1, it recruits HDAC3 and deacetylates histone 3 in the promoter of c-Jun, blocking gene expression. Importantly, this is enough to up-regulate Krox20 and start Schwann cell differentiation program–inducing myelin gene expression. Using conditional knockout mice, we also show that HDAC4 together with HDAC5 redundantly contribute to activate the myelin transcriptional program and the development of myelin sheath in vivo. We propose a model in which cAMP signaling shuttles class IIa HDACs into the nucleus of Schwann cells to regulate the initial steps of myelination in the peripheral nervous system.
38
Psilopatis, Iason, Kleio Vrettou, Florian Nima Fleckenstein e Stamatios Theocharis. "The Impact of Histone Modifications in Endometriosis Highlights New Therapeutic Opportunities". Cells 12, n. 9 (23 aprile 2023): 1227. http://dx.doi.org/10.3390/cells12091227.
Testo completoAbstract (sommario):
Endometriosis is a chronic disorder of the female reproductive system which afflicts a great number of women worldwide. Histone deacetylases (HDACs) prevent the relaxation of chromatin, thereby positively or negatively modulating gene transcription. The current review aims at studying the impact of histone modifications and their therapeutic targeting in endometriosis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The current manuscript represents the most comprehensive, up-to-date review of the literature focusing on the particular role of HDACs and their inhibitors in the context of endometriosis. HDAC1, HDAC2, HDAC3, Sirtuin 1, and Sirtuin 3, are the five most studied HDAC enzymes which seem to, at least partly, influence the pathophysiology of endometriosis. Both well-established and novel HDACIs could possibly represent modern, efficacious anti-endometriotic drug agents. Altogether, histone modifications and their therapeutic targeting have been proven to have a strong impact on endometriosis.
39
Hyndman, Kelly A., Malgorzata Kasztan, Luciano D. Mendoza e Sureena Monteiro-Pai. "Dynamic changes in histone deacetylases following kidney ischemia-reperfusion injury are critical for promoting proximal tubule proliferation". American Journal of Physiology-Renal Physiology 316, n. 5 (1 maggio 2019): F875—F888. http://dx.doi.org/10.1152/ajprenal.00499.2018.
Testo completoAbstract (sommario):
Deranged histone deacetylase (HDAC) activity causes uncontrolled proliferation, inflammation, fibrosis, and organ damage. It is unclear whether deranged HDAC activity results in acute kidney injury in the renal hypoperfusion model of bilateral ischemia-reperfusion injury (IRI) and whether in vivo inhibition is an appropriate therapeutic approach to limit injury. Male mice were implanted with intraperitoneal osmotic minipumps containing vehicle, the class I HDAC inhibitor, MS275, or the pan-HDAC inhibitor, trichostatin A (TSA), 3 days before sham/bilateral IRI surgery. Kidney cortical samples were analyzed using histological, immunohistochemical, and Western blotting techniques. HDAC-dependent proliferation rate was measured in immortalized rat epithelial cells and primary mouse or human proximal tubule (PT) cells. There were dynamic changes in cortical HDAC localization and abundance following IRI including a fourfold increase in HDAC4 in the PT. HDAC inhibition resulted in a significantly higher plasma creatinine, increased kidney damage, but reduced interstitial fibrosis compared with vehicle-treated IRI mice. HDAC-inhibited mice had reduced interstitial α-smooth muscle actin, fibronectin expression, and Sirius red-positive area, suggesting that IRI activates HDAC-mediated fibrotic pathways. In vivo proliferation of the kidney epithelium was significantly reduced in TSA-treated, but not MS275-treated, IRI mice, suggesting class II HDACs mediate proliferation. Furthermore, HDAC4 activation increased proliferation of human and mouse PTs. Kidney HDACs are activated during IRI with isoform-specific expression patterns. Our data point to mechanisms whereby IRI activates HDACs resulting in fibrotic pathways but also activation of PT proliferation and repair pathways. This study demonstrates the need to develop isoform-selective HDAC inhibitors for the treatment of renal hypoperfusion-induced injury.
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Mayr, Christian, Tobias Kiesslich, Sara Erber, Dino Bekric, Heidemarie Dobias, Marlena Beyreis, Markus Ritter et al. "HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer". Cancers 13, n. 15 (31 luglio 2021): 3862. http://dx.doi.org/10.3390/cancers13153862.
Testo completoAbstract (sommario):
Inhibition of histone deacetylases (HDACs) is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. Therefore, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition into a panel of eight established BTC cell lines. The screening results indicate a heterogeneous expression of HDACs across the studied cell lines. We next tested the effect of six established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis on cell viability of BTC cells and found that the effect (i) is dose- and cell-line-dependent, (ii) does not correlate with HDAC isoform expression, and (iii) is most pronounced for romidepsin (a class I HDACi), showing the highest reduction in cell viability with IC50 values in the low-nM range. Further analyses demonstrated that romidepsin induces apoptosis in BTC cells, reduces HDAC activity, and increases acetylation of histone 3 lysine 9 (H3K9Ac). Similar to BTC cell lines, HDAC 1/2 proteins were heterogeneously expressed in a cohort of resected BTC specimens (n = 78), and their expression increased with tumor grading. The survival of BTC patients with high HDAC-2-expressing tumors was significantly shorter. In conclusion, HDAC class I inhibition in BTC cells by romidepsin is highly effective in vitro and encourages further in vivo evaluation in BTC. In situ assessment of HDAC 2 expression in BTC specimens indicates its importance for oncogenesis and/or progression of BTC as well as for the prognosis of BTC patients.
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Minisini, Martina, Emiliano Dalla, Vanessa Tolotto e Claudio Brancolini. "Abstract B014: The role of HDAC-MEF2 axis in the epigenetic control of immune tumoral microenvironment". Cancer Research 82, n. 23_Supplement_2 (1 dicembre 2022): B014. http://dx.doi.org/10.1158/1538-7445.cancepi22-b014.
Testo completoAbstract (sommario):
Abstract Epigenetic mechanisms have a main impact on cancer regulation and on microenvironment control. In the context of leiomyosarcoma (LMS), a highly aggressive and immunologically cold cancer, class IIa histone deacetylases (HDACs) and myocyte enhancer factor (MEF2) form a repressive complex that leads to the reorganization of epigenetic landscape. We have recently described the effect of some HDAC inhibitors (HDACi) on chromatin organization and in particular the increase of H3K27Ac genome occupancy near TSS and promoter regions, caused by NKL-54, a HDAC1/2/3 selective inhibitor, and the re-expression of some chemokines can be observed after the treatment with TMP-195, a specific class IIa HDACi. The hypothesis of this project is that the HDAC-MEF2 complex represses the transcription of some immune genes that may have a major role in antitumor response through an epigenetic control of chromatin. To verify this proposal, we knocked-down (KD) MEF2A in SK-UT-1, a high grade LMS cell line, or we treated the same cells with NKL-54 and TMP-195. We compared the impact of MEF2A KD and HDACs inhibition on chemokines and cytokines release by RNA-seq and Luminex profiling, while H3K27ac levels obtained by ChIP-seq were used to quantify enhancers and super-enhancers activation. To evaluate the impact of MEF2A on LMS cells proliferation we performed a clonogenic assay. To test the effectiveness of class IIa HDACs inhibitors in vivo, we aim to generate a syngeneic model of LMS by transforming uterine smooth muscle cells with Large T and Small T antigen, p53175H and by knocking out (KO) ATRX and PTEN. The preliminary data show that KD of MEF2A leads to an increased expression and release of some chemokines and cytokines such as CXCL5, CXCL2 and CXCL8 in SK-UT-1 cells. Class IIa HDACs inhibition further enhances this effect. Furthermore, the absence of MEF2A causes a reduction of colonies formation compared with WT cells, pointing out the fundamental role of MEF2A in LMS cell proliferation. Finally, ChIP-seq analysis of the genomic location of CXCL2 and CXCL5 in HDAC4 and HDAC9 KO shows an increased H3K27Ac signal at the level of the regulative elements of the two genes, indicating the epigenetic reprogramming acting on these loci and achieved by HDACs impairment. High grade LMS are characterized by the formation of HDAC IIa and MEF2 repressive complexes at some specific genomic loci required to sustain LMS malignancy and possibly to weaken LMS immunogenicity. The ablation or the specific inhibition of class IIa HDACs lead to the release of MEF2A from this repressive complex and the subsequent establishment of a transcriptional open chromatin environment that would promote tumor immune infiltration and clearance. These preliminary data, together with previous evidence, highlight the role of HDAC-MEF2 in the context of LMS microenvironment organization, suggesting that the targeting of these partners can boost the immune system activity, and this can be exploited for the development of LMS therapies. Citation Format: Martina Minisini, Emiliano Dalla, Vanessa Tolotto, Claudio Brancolini. The role of HDAC-MEF2 axis in the epigenetic control of immune tumoral microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B014.
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Shobaki, Nour, Pankaj Gaur, Rahul Nadre, Vivek Verma, Peter Ordentlich, Lei Wang, Nazli Jafarzadeh et al. "Abstract LB566: Class 1 HDAC inhibition induces antitumor immunity by NF-kB-mediated enhanced metabolic fitness and generation of unique effector function enriched memory CD8 T cell subtype". Cancer Research 82, n. 12_Supplement (15 giugno 2022): LB566. http://dx.doi.org/10.1158/1538-7445.am2022-lb566.
Testo completoAbstract (sommario):
Abstract Histone/protein deacetylases (HDACs) are a class of enzymes that regulate gene expression and are involved in regulating the transcription process as well as regulating fundamental cellular processes such as proliferation, differentiation and development. Class I HDACs (which includes HDAC1, 2, 3, and 8) contribute in epigenetic regulations of T cell tolerance. Under anergic T cell condition, HDAC1 and HDAC2 are involved in the histone deacetylation. However, the role of HDACs in CD8 T cell function and differentiation is not well understood. Therefore, we aimed to understand the effect of HDAC inhibition (HDACi) on CD8 T cells phenotype and functionality by using Entinostat (ENT), a class I HDAC (HDAC1 and 3) inhibitor. We found that ENT induces strong immune-mediated anti-tumor effects in TC-1 and B16 tumor-bearing mice. Mechanistically, ENT modulated the tumor microenvironment through an increased infiltration of CD8 T cells, enhanced CD8 T cell antigen-specificity and CD8 T cell functionality represented by interferon gamma (IFN-γ) and granzyme B (GrB) secretion. Our in vitro and in vivo data also indicate that ENT enhances central memory phenotype (CD62L+, CD44+) of CD8 T cells. We also found that ENT-treated CD8 T cells have distinct metabolic phenotype compared to activated CD8 T cells. Specifically, these cells relied more on amino acid metabolism while, unexpectedly, they had lower fatty acid uptake with enhanced mitochondrial potential (TMRM). Interestingly, ENT-induced central memory CD8 T cells also showed increased mitochondrial potential as well as reliance on amino acid metabolism. Therefore, ENT treatment induced memory cells with a unique phenotype different from the classical memory CD8 T cells with enhanced effector functions and reliance on distinct metabolic pathways. Furthermore, ENT-treated CD8 T cells have higher peaks at H3K27Ac site compared to the control. Since these peaks are mostly associated with genes such as IFN-γ, GrB, Pim1, EOMES, and IL-2, the known canonical target genes of NF-κB in CD8 T cells, we further dissected the role of NF-κB in these ENT-mediated effects. First, motif analysis showed that NF-κB binding motif is enriched in differential H3K27Ac sites associated with HDACi. Next, flow cytometry and immunofluorescence analysis showed that although ENT does not increase total NF-κB levels in CD8 T cells, it enhances its binding to the chromatin due to enhanced gene accessibility. This research highlights the significance of epigenetic modulation in enhancing the immune-mediated anti-tumor effects and provide fundamental understanding of the mechanism of action of HDAC inhibition in CD8 T cells. Citation Format: Nour Shobaki, Pankaj Gaur, Rahul Nadre, Vivek Verma, Peter Ordentlich, Lei Wang, Nazli Jafarzadeh, Wael Traboulsi, Mikayel Mkrtichyan, Seema Gupta, Samir N. Khleif. Class 1 HDAC inhibition induces antitumor immunity by NF-kB-mediated enhanced metabolic fitness and generation of unique effector function enriched memory CD8 T cell subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB566.
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Mankidy, Rishikesh, Douglas V. Faller, Michael S. Boosalis, Regine Bohacek e Susan P. Perrine. "Mechanisms of γ-Globin Gene Promoter Activation by HBF-Inducing Short Chain Fatty Acid Derivatives." Blood 106, n. 11 (16 novembre 2005): 826. http://dx.doi.org/10.1182/blood.v106.11.826.826.
Testo completoAbstract (sommario):
Abstract High-level γ-globin gene expression for definitive therapy of beta globin disorders likely requires γ-globin gene promoter activation, dissociation of repressor complexes, and/or local chromatin modification. To define the molecular mechanisms employed by high-potency γ-globin inducers, the effects of butyrate on transcriptional co-regulatory protein recruitment to the human γ- and β-globin gene promoters were defined and compared to those of novel SCFAD γ-globin inducers recently identified through computational modeling. One particularly potent SCFAD inducer, RB7, which has no inhibitory effect on class I HDAC enzymes (HDAC1, HDAC2, and HDAC3), demonstrated 5-fold induction, (2.5 to 3-fold greater γ-globin gene-inducing activity than butyrate), in a transcriptional reporter assay which detects only strong γ-globin gene inducers. Chromatin immunoprecipitation (ChIP) assays performed on the integrated human gamma and beta globin gene promoters demonstrated that RB7, butyrate, and other transcriptionally-active SCFADs, induced dissociation of HDAC-3, and its adaptor protein NCoR, from the γ-globin gene promoter, with no such effect on the β-globin promoter, coincident with recruitment of RNA Polymerase II to the γ-globin promoter and initiation of γ-globin transcription. In a reciprocal fashion, as HDAC-3 dissociated, the chromatin-modifying ATPases Brg-1 and Brm were recruited specifically to the γ-globin gene promoter in response to the active SCFADs. The ability of the novel SCFADs to induce dissociation of HDAC-3 (but not HDAC-1 or -2) from the γ-globin promoter was proportional to the degree of γ-globin promoter induction by these agents. Knockdown of HDAC-3 by siRNA induced transcription of γ-globin specifically, demonstrating the functional importance of the activity of SCFADS in dissociating HDAC-3 from the γ-globin gene promoter. These studies demonstrate new dynamic alterations in transcriptional regulatory complexes specifically-associated with high-level activation of γ-globin and also identify essential molecular targets for future therapeutic interventions.
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Shearstone, Jeffrey R., John H. van Duzer, Simon S. Jones e Matthew Jarpe. "Pharmacological Inhibition Of Histone Deacetylase (HDAC) 1, 2 Or 3 Have Distinct Effects On Cellular Viability, Erythroid Differentiation, and Fetal Globin (HbG) Induction". Blood 122, n. 21 (15 novembre 2013): 564. http://dx.doi.org/10.1182/blood.v122.21.564.564.
Testo completoAbstract (sommario):
Abstract Induction of HbG is an established therapeutic strategy for the treatment of sickle cell disease (SCD), and could also be effective in treating beta-thalassemia (bT). Genetic ablation of HDAC1 or HDAC2, but not HDAC3, results in the induction of HbG expression (Bradner JE, Proc Natl Acad Sci, 2010). Furthermore, we have previously shown that selective chemical inhibitors of HDAC1 and 2 elicit a dose and time dependent induction of HbG mRNA and fetal hemoglobin (HbF) protein in cultured human CD34+ bone marrow cells undergoing erythroid differentiation (Shearstone JS, ASH Annual Meeting Abstracts, 2012). While a variety of selective HDAC inhibitors have been used successfully to induce HbF, further clinical development has been limited by variable efficacy and concerns over off-target side-effects observed in clinical trials, potentially due to inhibition of HDAC3. Additionally, it remains to be determined if HDAC1 or HDAC2 is the preferred therapeutic target. In this work we present data that investigates the effects of selective inhibitors of HDAC1, 2, or 3 on cytotoxicity, erythroid differentiation, and HbG induction in cultured human CD34+ bone marrow cells. Acetylon Pharmaceuticals has generated a library of structurally distinct compounds with a range of selectivity for each of HDAC1, 2, or 3 (Class I HDAC) as determined in a biochemical assay platform. From our initial chemical series, we identified ACY-822 as a Class I HDAC inhibitor with IC50 values of 5, 5, and 8 nM against HDAC1, 2, and 3, respectively. In contrast, ACY-1112 is 30-fold selective for HDAC1 and 2, with IC50 values of 38, 34, and 1010 nM against HDAC1, 2, and 3, respectively. Treatment of cells for 4 days with ACY-822 (1 μM) resulted in a 20-fold decrease in cell viability, while ACY-1112 (1 μM) treatment resulted in a minimal reduction in viability (1.2-fold) and a 2-fold increase in the percentage of HbG relative to other beta-like globin transcripts. This result suggests that pharmacological inhibition of HDAC3 is cytotoxic and is consistent with the therapeutic rationale for the design selective inhibitors of HDAC1 and 2. To investigate if HDAC1 or HDAC2 is the preferred therapeutic target, we utilized a second series of structurally distinct compounds. We identified ACY-957 as an HDAC1/2 selective compound biased towards HDAC1 with IC50 values of 4, 15, and 114 nM for HDAC1, 2, and 3, respectively. In contrast ACY-1071 showed balanced HDAC1 and 2 selectivity with IC50 values of 27, 24, and 247 nM for HDAC1, 2, and 3, respectively. Treatment of cells for 6 days with 1 μM of ACY-957 or ACY-1071 resulted in a 3-fold increase in the percentage of HbG relative to other beta-like globin transcripts. However, we found that ACY-957 treatment resulted in an approximately 3-fold decrease in cell viability after 6 days of treatment, while ACY-1071 treatment resulted in a minimal reduction (1.2-fold) in cell viability. Decreased cell viability observed with ACY-957 was associated with a reduction of cells positive for the erythroid differentiation markers CD71 and glycophorinA. This result is consistent with the Mx-Cre mouse model where HDAC1KO; HDAC2het had reduced numbers of erythrocytes, thrombocytes, and total bone marrow cells, while the HDAC1het; HDAC2KO was unaffected (Wilting RH, EMBO Journal, 2010). Our results suggest that compounds with a pharmacological profile of increased selectivity towards HDAC2 inhibition versus HDAC1 may be less cytotoxic and minimize effects on differentiation, while still inducing HbG in human CD34+ bone marrow cells. Disclosures: Shearstone: Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. van Duzer:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Jarpe:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership.
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Bradbury, Charlotte A., Farhat L. Khanim, Priyanka Mehta, Rachel E. Hayden, Charles F. Craddock, Chris M. Bunce e Bryan M. Turner. "Characterisation of Histone Deacetylase (HDAC) Expression Profiles in Acute Myeloid Leukaemia: A Basis for the Development of Targeted Therapy Using Histone Deacetylase Inhibitors." Blood 104, n. 11 (16 novembre 2004): 1123. http://dx.doi.org/10.1182/blood.v104.11.1123.1123.
Testo completoAbstract (sommario):
Abstract Post-translational modifications of chromatin structure are recognised as having a potential role in the pathogenesis of acute myeloid leukaemia (AML). Histone deacetylases play a central role in determining the acetylation status of histones and are emerging as novel targets in AML therapy. Histone deacetylase inhibitors (HDIs) inhibit growth of primary AML blasts in vitro and demonstrate clinical activity in patients with relapsed AML. To date, three major classes of HDACs have been characterised which differ in their susceptibility to HDIs. However, little is known of the pattern of HDAC expression in AML and this limits the rational use of HDIs in this disease. We have analysed the pattern of class I, II and III HDAC expression in AML cell lines, primary AML blasts and CD34+ selected progenitors from cord blood and normal donors by real time quantitative PCR(RT-PCR). RT-PCR analyses demonstrated consistently increased expression in AML blasts of two HDACs compared with proliferating CD34+ve cells from cord blood (n=5) . HDAC2 (class I HDAC) was more highly expressed in 3/3 myeloid cell lines and 20/24 primary AML samples, compared to cord blood CD 34+ve cells. SIRT1 (class III HDAC) was also more highly expressed in 3/3 myeloid cell lines and 24/24 primary AMLs. In contrast, no marked differences were detected in expression of HDAC1, 3, 4, 5, 6, 7, 9, 10, 11 and SIRT 2–6. We therefore studied the impact of sodium valproate (SV), an HDI with reported activity in AML, on HDAC activity and expression. SV treatment resulted in time and dose dependent increases in histone acetylation and specific methylation at H3K4, in both AML cell lines and primary AML cells. We have shown that the mechanism of the increased methylation at H3K4 is partly a result of the preference of the methyltransferase enzyme for acetylated histones. Using quantitative RT-PCR we found that SV treatment of HL-60 cells resulted in increased expression of the gene for MLL, an enzyme known to be capable of methylating H3K4. These changes in chromatin were associated with dose dependent cell killing. Significant (p<0.001, n=10) in vitro killing of primary AML blasts was observed at 1 mM SV and killing was enhanced by the addition of ATRA. However, histone modifications were observed in HL-60 cells at doses that had little effect upon cell viability or proliferation. We have immunoprecipitated complexes containing HDACs 1, 2 and 3 and assayed their enzymatic activity using a tritium labelled H4 peptide substrate. By this method, 1mM SV was potent at inhibiting HDACs 1, 2 and 3 activity. We have also studied the effects of SV on HDAC expression (all three classes) by RT-PCR in HL60 cells at 15 mins, 1h, 4h and 8h. A small number of HDACs were consistently and significantly upregulated by treatment with SV, TSA, Butyrate and SAHA. In contrast, the expression levels of HDAC2 and SIRT1 were relatively unchanged. These changes in HDAC expression may contribute to HDI resistance with continuous therapy. These data provide information which may be of value in determining choice of HDACis in Phase I/II studies in AML. They also identify increased histone methylation as a potentially important outcome of HDI treatment.
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Yuliana, Ana, Huei-Fen Jheng, Satoko Kawarasaki, Wataru Nomura, Haruya Takahashi, Takeshi Ara, Teruo Kawada e Tsuyoshi Goto. "β-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte". International Journal of Molecular Sciences 19, n. 8 (17 agosto 2018): 2436. http://dx.doi.org/10.3390/ijms19082436.
Testo completoAbstract (sommario):
Browning of adipose tissue has been prescribed as a potential way to treat obesity, marked by the upregulation of uncoupling protein 1 (Ucp1). Several reports have suggested that histone deacetylase (HDAC) might regulate Ucp1 by remodelling chromatin structure, although the mechanism remains unclear. Herein, we investigate the effect of β-adrenergic receptor (β-AR) activation on the chromatin state of beige adipocyte. β-AR-stimulated Ucp1 expression via cold (in vivo) and isoproterenol (in vitro) resulted in acetylation of histone activation mark H3K27. H3K27 acetylation was also seen within Ucp1 promoter upon isoproterenol addition, favouring open chromatin for Ucp1 transcriptional activation. This result was found to be associated with the downregulation of class I HDAC mRNA, particularly Hdac3 and Hdac8. Further investigation showed that although HDAC8 activity decreased, Ucp1 expression was not altered when HDAC8 was activated or inhibited. In contrast, HDAC3 mRNA and protein levels were simultaneously downregulated upon isoproterenol addition, resulting in reduced recruitment of HDAC3 to the Ucp1 enhancer region, causing an increased H3K27 acetylation for Ucp1 upregulation. The importance of HDAC3 inhibition was confirmed through the enhanced Ucp1 expression when the cells were treated with HDAC3 inhibitor. This study highlights the novel mechanism of HDAC3-regulated Ucp1 expression during β-AR stimulation.
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Mishra, Anjali, Krista M. D. La Perle, Laura Sullivan, Gregory H. Sams, Douglas P. Curphey, Kathleen McConnell, Jun Qi et al. "Increased Expression Of IL-15 Promotes Cutaneous T-Cell Lymphomagenesis Via The Upregulation Of Histone Deacetylases: Evidence For Successful Preclinical Targeting". Blood 122, n. 21 (15 novembre 2013): 1826. http://dx.doi.org/10.1182/blood.v122.21.1826.1826.
Testo completoAbstract (sommario):
Abstract Cutaneous lymphoma is a heterogeneous group of neoplasms of skin-homing malignant lymphocytes. Cutaneous T-cell Lymphoma (CTCL) represents 70-80% of all cutaneous lymphoma and its pathogenesis is largely unknown. Previous studies have shown that interleukin (IL)-15 is a potent stimulant and growth factor for CTCL cells in vitro. In order to investigate the intrinsic levels of IL-15 in CTCL patients, malignant CD4+ T-cells were analyzed for expression of IL-15. Relative quantitation of IL-15 transcript in patient vs normal donor (ND) CD4+ cells showed overexpression of IL-15 in patients (fold increase mean ± SD = 5.36 ± 4.39, N=13, P<0.001). Increase in IL-15 transcript was directly proportional to disease severity in patients i.e. fold increase mean ± SD in IL-15 in Stage I =3.28 ± 1.42, N=3 each, P=0.0047 vs. Stage III patients = 7.42 ± 1.30, N=3 each, P=0.0073. Further, cutaneous lesions in patients stained positive for IL-15 protein in atypical lymphoid cells and Pautrier's microabscess. We next investigated the role of IL-15 in CTCL development using IL-15 transgenic (tg) mice. Within 4-6 weeks of birth, IL-15 tg mice developed extensive patch/plaque skin lesions, progressive alopecia, and severe pruritus. Adult IL-15 tg mice developed extensive involvement with cutaneous lymphoma that was fatal in 100% of the mice (P=0.0003). Antibodies staining revealed that CD4+ skin resident T-cells in IL-15 tg mice were CD3+CD62L-CD44hiCCR4+CLA+. Flow cytometric analysis of single cell suspension of skin showed ∼25-fold increase in CD3+ T-cells in IL-15 tg compared to WT controls (Mean ± SD of absolute number of cells= 3.80 ± 6.97, N=14 vs. 0.15 ± 0.26, N=8 respectively, P<0.001). Lymphoma cells from IL-15 tg mouse skin engrafted and mimicked the primary disease in immune deficient SCID mice upon adoptive transfer. CD4+ T-cells from CTCL patients showed increased histone deacetylases (HDAC) 1, HDAC2 and HDAC6 transcripts over ND CD4+ T-cells and immunoblot analysis of ND CD4+ T-cells exposed to 100ng/ml IL-15 showed upregulation of HDAC1, HDAC2 and HDAC6 ex vivo. IL-15 stimulation of ND CD4+ T-cells resulted in loss of expression of the downstream HDAC1/2 target tumor suppressor, p21 in vitro, and knock down of HDAC6 in IL-15 stimulated ND CD4+ T-cells inhibited their migration in vitro; suggesting that IL-15 mediated upregulation of HDAC6 is critical for T-cell migration. Considering these observations, we used specific novel HDAC inhibitors (HDACi) to target HDAC1/2 (JQ12) and/or HDAC6 (WT161) in IL-15 tg mice to determine if we could prevent CTCL in vivo. IL-15 tg mice were treated with 50mg/kg of either or both the inhibitors, 5 days/week for 4 weeks (n=4 each). While placebo treated IL-15 tg mice progressively developed lesions during the course of treatment, IL-15 tg mice treated with JQ12 and/or WT161 showed no clinical signs of disease. This was further corroborated by histopathology analysis of skin sections from treated mice (Figure 1). Thus, our data suggest that inhibiting HDAC1, HDAC2 and/or HDAC6 pathways inhibits the development of CTCL in IL-15tg mice. In addition to the prevention study, we assessed the ability of a novel pan-HDACi, AR42, to treat active and progressive disease in our model. IL-15 tg mice with established CTCL were randomized to receive either AR42 or placebo feed (n=6 each) for 12 days. The IL-15 tg mice treated with AR42 showed remarkable improvement compared to the placebo mice whose disease progressed. Histopathology analysis of the AR42-treated IL-15 tg mice showed an impressive clearance of the CD3+ and CD4+ atypical lymphocytic infiltrate compared to placebo-treated mice (Figure 2). In summary we provide evidence that IL-15 has a causal role in the pathogenesis of CTCL; that IL-15 tg mice provide a novel model for studying disease pathogenesis and for evaluating potential therapies; that HDACi targeting specific HDACs may be effective in preventing CTCL and a novel pan-HDACi can reverse severe dermatologic disease in this CTCL model. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures: No relevant conflicts of interest to declare.
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Soflaei, Sara Saffar, Amir Abbas Momtazi-Borojeni, Muhammed Majeed, Giuseppe Derosa, Pamela Maffioli e Amirhossein Sahebkar. "Curcumin: A Natural Pan-HDAC Inhibitor in Cancer". Current Pharmaceutical Design 24, n. 2 (5 aprile 2018): 123–29. http://dx.doi.org/10.2174/1381612823666171114165051.
Testo completoAbstract (sommario):
Background: Histone deacetylases (HDACs) are a group of histone modification enzymes with pivotal role in disease pathogenesis especially in cancer development. Increased activity of certain types of HDACs and positive effects of HDAC inhibition has been shown in several types of cancers. Furthermore, few HDAC inhibitors have been approved by the FDA for cancer treatment, and this has generated interest in finding new HDAC inhibitors as potential anti-cancer agents. Curcumin, a natural polyphenol extracted from turmeric, is a safe and bioactive phytochemical with a wide range of molecular targets and pharmacological activities including promising anti-cancer properties. Methods: A systematic literature search using appropriate keywords was made to identify articles reporting the modulatory effect of curcumin on HDACs in different types of cancer in vitro and in vivo. Results: HDACs have emerged as novel targets of curcumin that their modulation may contribute to the putative anti-cancer effects of curcumin. Curcumin inhibits HDAC activity, and down-regulates the expression of HDAC types 1, 2, 3, 4, 5, 6, 8 and 11 in different cancer cell lines and mice, while the activity and expression of HDAC2 have been reported to be up-regulated by curcumin in COPD and heart failure models. Conclusion: Available in vitro and in vivo data are encouraging and in favor of the HDAC inhibitory activity of curcumin but clinical evidence on the efficacy of curcumin as an adjunct treatment in cancer patients is lacking.
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Alamdari, Nima, Ira J. Smith, Zaira Aversa e Per-Olof Hasselgren. "Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, n. 2 (agosto 2010): R509—R520. http://dx.doi.org/10.1152/ajpregu.00858.2009.
Testo completoAbstract (sommario):
Muscle wasting during sepsis is in part regulated by glucocorticoids. In recent studies, treatment of cultured muscle cells in vitro with dexamethasone upregulated expression and activity of p300, a histone acetyl transferase (HAT), and reduced expression and activity of the histone deacetylases-3 (HDAC3) and -6, changes that favor hyperacetylation. Here, we tested the hypothesis that sepsis and glucocorticoids regulate p300 and HDAC3 and -6 in skeletal muscle in vivo. Because sepsis-induced metabolic changes are particularly pronounced in white, fast-twitch skeletal muscle, most experiments were performed in extensor digitorum longus muscles. Sepsis in rats upregulated p300 mRNA and protein levels, stimulated HAT activity, and reduced HDAC6 expression and HDAC activity. The sepsis-induced changes in p300 and HDAC expression were prevented by the glucocorticoid receptor antagonist RU38486. Treatment of rats with dexamethasone increased expression of p300 and HAT activity, reduced expression of HDAC3 and -6, and inhibited HDAC activity. Finally, treatment with the HDAC inhibitor trichostatin A resulted in increased muscle proteolysis and expression of the ubiquitin ligase atrogin-1. Taken together, our results suggest for the first time that sepsis-induced muscle wasting may be regulated by glucocorticoid-dependent hyperacetylation caused by increased p300 and reduced HDAC expression and activity. The recent development of pharmacological HDAC activators may provide a novel avenue to prevent and treat muscle wasting in sepsis and other catabolic conditions.
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Kafeel, Muhammad I., Boris Avezbakiyev, Chi Chen, Yiwu Sun, Chenthil Rathnasabapathy, M. Kalavar, Zili He, Jack Burton, Stephen M. Lichter e Jen-Chin Wang. "Histone Deacetylase Activity In Chronic Lymphocytic Leukemia." Blood 116, n. 21 (19 novembre 2010): 4622. http://dx.doi.org/10.1182/blood.v116.21.4622.4622.
Testo completoAbstract (sommario):
Abstract Abstract 4622 Elevated histone deacetylase (HDAC) enzyme levels have been described in patients with carcinoma and leukemia. Using HDAC inhibitor (HDACi) to treat carcinoma has been promising and is currently undergoing intense research. In order to be better in using HDACi to treat chronic lymphocytic leukemia (CLL), HDAC isoenzyme levels were measured in 32 patients with CLL and compared with 17 normal volunteer controls. Peripheral blood CD20+ cells from patients with CLL and normal volunteer controls were isolated by using Progenitor Cell Isolation Kits (Miltenyi Biotec, Auburn, CA). Isolated CD20+ cells were confirmed by flow cytometry studies to have more than 92% purity. Patient and control CD20+ cells were then lysed in denaturation buffer. Total RNA was extracted, then cDNAs were prepared and quantitative RT-PCR was performed using premixed primer and FAM- and TAMRA-labeled probes obtained from ABI. The results showed: 1) HDAC1, -3, -6, -7, -9, and -10 and SIRT1, -2, and -6 were significantly over-expressed, suggesting that, in CLL, elevated HDAC activity are not restricted to one class. Therefore, HDAC inhibitor therapy may need to be directed to more than one specific class of HDAC; 2) Patients with ZAP70+ were associated with more advanced Rai clinical stage and higher HDAC activity than Zap70– patients and HDAC activity were correlated to the expression levels of CD44 and Pin1, suggesting that higher HDAC values may indicate a poor prognosis and more advanced disease stage. Disclosures: No relevant conflicts of interest to declare.