scholarly journals Cross Talk between Histone Deacetylase 4 and STAT6 in the Transcriptional Regulation of Arginase 1 during Mouse Dendritic Cell Differentiation

2014 ◽  
Vol 35 (1) ◽  
pp. 63-75 ◽  
Author(s):  
Quan Yang ◽  
Jianyang Wei ◽  
Limei Zhong ◽  
Maohua Shi ◽  
Pan Zhou ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Cross Talk ◽  
Transcriptional Activation ◽  
Hdac Inhibitors ◽  
Ectopic Expression ◽  
Suppressor Cells ◽  
Dendritic Cell Differentiation ◽  
Arginase 1 ◽  
Histone Deacetylase 4 ◽  
Macrophage Colony

l-Arginine andl-arginine-metabolizing enzymes play important roles in the biology of some types of myeloid cells, including macrophage and myeloid-derived suppressor cells. In this study, we found evidence that arginase 1 (Arg1) is required for the differentiation of mouse dendritic cells (DCs). Expression of Arg1 was robustly induced during monocyte-derived DC differentiation. Ectopic expression of Arg1 significantly promoted monocytic DC differentiation in a granulocyte-macrophage colony-stimulating factor culture system and also facilitated the differentiation of CD8α+conventional DCs in the presence of Flt3 ligand. Knockdown of Arg1 reversed these effects. Mechanistic studies showed that the induced expression of Arg1 in differentiating DCs was caused by enhanced recruitment of histone deacetylase 4 (HDAC4) to the Arg1 promoter region, which led to a reduction in the acetylation of both the histone 3 and STAT6 proteins and subsequent transcriptional activation of Arg1. Further investigation identified a novel STAT6 binding site within the Arg1 promoter that mediated its regulation by STAT6 and HDAC4. These observations suggest that the cross talk between HDAC4 and STAT6 is an important regulatory mechanism of Arg1 transcription in DCs. Moreover, overexpression of Arg1 clearly abrogated the ability of HDAC inhibitors to suppress DC differentiation. In conclusion, we show that Arg1 is a novel regulator of myeloid DC differentiation.

scholarly journals Histone deacetylase inhibitors suppress IL-2–mediated gene expression prior to induction of apoptosis

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1490-1495 ◽  
Author(s):  
Yuko Koyama ◽  
Masaaki Adachi ◽  
Masuo Sekiya ◽  
Mutsuhiro Takekawa ◽  
Kohzoh Imai
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
K562 Cells ◽  
Histone Hyperacetylation ◽  
Induced Apoptosis ◽  
Do So

Histone deacetylase (HDAC) inhibitors can induce transcriptional activation of a number of genes and induce cellular differentiation as histone acetylation levels increase. Although these inhibitors induce apoptosis in several cell lines, the precise mechanism by which they do so remains obscure. This study shows that HDAC inhibitors, sodium butyrate and trichostatin A (TSA), abrogate interleukin (IL)-2–mediated gene expression in IL-2–dependent cells. The HDAC inhibitors readily induced apoptosis in IL-2–dependent ILT-Mat cells and BAF-B03 transfectants expressing the IL-2 receptor βc chain, whereas they induced far less apoptosis in cytokine-independent K562 cells. However, these inhibitors similarly increased acetylation levels of histones in both cells. Although histone hyperacetylation is believed to lead to transcriptional activation, the results showed an abrogation of IL-2–mediated induction of c-myc,bag-1, and LC-PTP gene expression. This observed abrogation of gene expression occurred prior to phosphatidylserine externalization, a process that occurs in early apoptotic cells. Considering the biologic role played by IL-2–mediated gene expression in cell survival, these data suggest that its abrogation may contribute to the apoptotic process induced by HDAC inhibitors.

scholarly journals Histone Deacetylase Inhibitors in Cell Pluripotency, Differentiation, and Reprogramming

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Androniki Kretsovali ◽  
Christiana Hadjimichael ◽  
Nikolaos Charmpilas
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Ectopic Expression ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Stem Cell Differentiation ◽  
Induced Pluripotent

Histone deacetylase inhibitors (HDACi) are small molecules that have important and pleiotropic effects on cell homeostasis. Under distinct developmental conditions, they can promote either self-renewal or differentiation of embryonic stem cells. In addition, they can promote directed differentiation of embryonic and tissue-specific stem cells along the neuronal, cardiomyocytic, and hepatic lineages. They have been used to facilitate embryo development following somatic cell nuclear transfer and induced pluripotent stem cell derivation by ectopic expression of pluripotency factors. In the latter method, these molecules not only increase effectiveness, but can also render the induction independent of the oncogenes c-Myc and Klf4. Here we review the molecular pathways that are involved in the functions of HDAC inhibitors on stem cell differentiation and reprogramming of somatic cells into pluripotency. Deciphering the mechanisms of HDAC inhibitor actions is very important to enable their exploitation for efficient and simple tissue regeneration therapies.

scholarly journals Histone Deacetylase Activity Regulates Chemical Diversity in Aspergillus

2007 ◽  
Vol 6 (9) ◽  
pp. 1656-1664 ◽  
Author(s):  
E. Keats Shwab ◽  
Jin Woo Bok ◽  
Martin Tribus ◽  
Johannes Galehr ◽  
Stefan Graessle ◽  
...  
Keyword(s):  
Small Molecules ◽  
Aspergillus Nidulans ◽  
Histone Deacetylase ◽  
Secondary Metabolite ◽  
Filamentous Fungi ◽  
Small Molecule ◽  
Transcriptional Activation ◽  
Hdac Inhibitors ◽  
Gene Clusters ◽  
Chemical Diversity

ABSTRACT Bioactive small molecules are critical in Aspergillus species during their development and interaction with other organisms. Genes dedicated to their production are encoded in clusters that can be located throughout the genome. We show that deletion of hdaA, encoding an Aspergillus nidulans histone deacetylase (HDAC), causes transcriptional activation of two telomere-proximal gene clusters—and subsequent increased levels of the corresponding molecules (toxin and antibiotic)—but not of a telomere-distal cluster. Introduction of two additional HDAC mutant alleles in a ΔhdaA background had minimal effects on expression of the two HdaA-regulated clusters. Treatment of other fungal genera with HDAC inhibitors resulted in overproduction of several metabolites, suggesting a conserved mechanism of HDAC repression of some secondary-metabolite gene clusters. Chromatin regulation of small-molecule gene clusters may enable filamentous fungi to successfully exploit environmental resources by modifying chemical diversity.

Histone deacetylase inhibitors suppress IFNα-induced up-regulation of promyelocytic leukemia protein

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1373-1380 ◽  
Author(s):  
Jana Vlasáková ◽  
Zora Nováková ◽  
Lenka Rossmeislová ◽  
Michal Kahle ◽  
Pavel Hozák ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Eukaryotic Cell ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Interferon Α

Abstract Promyelocytic leukemia nuclear bodies (PML NBs), the structural domains of the eukaryotic cell nucleus, play a role in cancer and apoptosis, and their involvement in antiviral mechanisms mediated by interferons (IFNs) is proposed. IFNs dramatically increase the transcription of the PML gene. In this study, we have shown that the response of 2 structural PML NB components, PML and Sp100, to interferon-α (IFNα) was suppressed in cells simultaneously treated with histone deacetylase (HDAC) inhibitors (trichostatin A, sodium butyrate, MS-275, SAHA, and valproic acid). Trichostatin A (TSA) blocked the increase of PML NB number and suppressed up-regulation of PML mRNA and protein levels in several human cell lines and in normal diploid skin fibroblasts. Moreover, IFNα induction of IRF-1 was also inhibited by TSA, although incompletely. Analysis of cellular fractions did not show any defects in cytoplasmic-nuclear transport of STAT2, a component of transcription factor ISGF3 responsible for IFNα/β-dependent gene transcription. Moreover, chromatin immunoprecipitation showed that after IFNα stimulation STAT2 binds to ISRE element of PML promoter even in the presence of TSA and thus excluded STAT2-dependent mechanism of TSA effect. These results indicate that the action of histone deacetylases is necessary for the full transcriptional activation of IFNα-stimulated genes.

scholarly journals Histone deacetylase inhibitors suppress IL-2–mediated gene expression prior to induction of apoptosis

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1490-1495 ◽  
Author(s):  
Yuko Koyama ◽  
Masaaki Adachi ◽  
Masuo Sekiya ◽  
Mutsuhiro Takekawa ◽  
Kohzoh Imai
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
K562 Cells ◽  
Histone Hyperacetylation ◽  
Induced Apoptosis ◽  
Do So

Abstract Histone deacetylase (HDAC) inhibitors can induce transcriptional activation of a number of genes and induce cellular differentiation as histone acetylation levels increase. Although these inhibitors induce apoptosis in several cell lines, the precise mechanism by which they do so remains obscure. This study shows that HDAC inhibitors, sodium butyrate and trichostatin A (TSA), abrogate interleukin (IL)-2–mediated gene expression in IL-2–dependent cells. The HDAC inhibitors readily induced apoptosis in IL-2–dependent ILT-Mat cells and BAF-B03 transfectants expressing the IL-2 receptor βc chain, whereas they induced far less apoptosis in cytokine-independent K562 cells. However, these inhibitors similarly increased acetylation levels of histones in both cells. Although histone hyperacetylation is believed to lead to transcriptional activation, the results showed an abrogation of IL-2–mediated induction of c-myc,bag-1, and LC-PTP gene expression. This observed abrogation of gene expression occurred prior to phosphatidylserine externalization, a process that occurs in early apoptotic cells. Considering the biologic role played by IL-2–mediated gene expression in cell survival, these data suggest that its abrogation may contribute to the apoptotic process induced by HDAC inhibitors.

Down-Regulation of Microrna 223 and 148a Mediates Resistance of Human Acute Myeloid Leukemia Cells to Pan-Histone Deacetylase (HDAC) Inhibitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2401-2401
Author(s):  
Jianguang Chen ◽  
Veena Kandaswamy ◽  
Warren Fiskus ◽  
Yongchao Wang ◽  
Rekha Rao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Myeloid Leukemia ◽  
Hdac Inhibitors ◽  
Ectopic Expression ◽  
K562 Cells ◽  
Methyl Transferase ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Abstract 2401 Poster Board II-378 MicroRNA (miR) alterations are highly involved in the pathogenesis of leukemia. However, the role of miRs in de novo or acquired resistance of cancer cells to therapeutic agents has not been fully elucidated. Recently, we reported the isolation and characterization of HL-60/LR cells, derived from human acute myeloid leukemia HL-60 cells, that are resistant to pan-histone deacetylase (HDAC) inhibitors (HDIs), including vorinostat and panobinostat (Blood. 2008; 112: 2896). To explore the role of miRs in acquiring resistance to HDIs, we performed a miR microarray analysis of the parental HL-60 and HL-60/LR cells. Compared to HL-60 cells, expression of thirteen microRNAs were discovered to be significantly increased (> 4-fold) and fourteen miRs were markedly down-regulated (> 4-fold) in HL-60/LR cells. Alterations in the expression of three of the most promising upregulated (miR-21, miR-126 and miR-146a) and down-regulated (miR-223, miR-148a and miR-342) miRs were confirmed by Q-PCR in HL-60/LR cells. The expression of miR-223, miR-148a and miR-342 was also significant lower in the relatively HDI-resistant K562 cells as compared to HDI-sensitive U937 and HL-60 cells. Conversely, miR-126 and miR-146a expressions were higher in K562 cells compared to U937 and HL-60 cells. Short term (24 hours) treatment with panobinostat (10 to 50 nM) did not alter the expression of miR-223 or miR-148a expression in HL-60 cells. As compared to treatment with either agent alone, co-treatment with the histone methyl transferase EZH2 antagonist 3-deazaneplanocin (DZnep, 1.0 uM) and DNA methyl transferase inhibitor decitabine (2.0 uM) induced miR-223 and miR-148a levels and mediated apoptosis of HL-60/LR cells, suggesting that an epigenetic silencing mechanism(s) may be involved in the down-modulation of miR-223 and miR-148a in HL-60/LR cells. To determine whether the alterations in the miR levels were mechanistically involved in conferring resistance to HDIs, we engineered through retroviral transduction stable ectopic expressions of miR-223, miR-148a and miR-342 into HL-60/LR cells and miR-21 and miR-146a into HL-60 cells. Ectopic expression of miR-223 and miR-148a significantly increased the sensitivity of HL-60/LR cells to panobinostat and vorinostat. In contrast, re-expression of miR-342 had an insignificant effect on HDI sensitivity. Increased expression of miR-21 and miR-146a did not confer resistance to the HDIs in HL-60 and U937 cells. Next, by Western analyses, we compared the expression levels of several of the predicted target proteins of miR-223 and miR-148a, (as predicted by the computer programs TargetScan and picTAR), in HL-60 versus HL-60/LR cells, as well as in the HL-60/LR cells with stable ectopic expression of miR-223 and miR-148a. Several candidate proteins including GRP94, Ribosomal protein S6 kinase MSK1, MEF2C and DNMT1 showed higher level of expression in HL-60/LR versus HL-60 and were down-regulated in miR-223 or miR-148a transduced HL-60/LR cells, suggesting that these proteins may confer resistance against HDI. Parenthetically, miR-223 was shown to be a myeloid-specific miR which negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR-223 mutant mice have an expanded granulocytic compartment resulting from an increase in the number of granulocyte progenitors. In summary, our observations indicate that high miR-223 and miR-148a levels may be predictive biomarkers for sensitivity to HDIs in human AML cells. Additionally, induction of miR-223 and miR-148a by EZH2 antagonist may increase sensitivity and overcome resistance to HDIs in human AML cells. Targeting the levels and/or activity of the miR-223 and miR-148a target proteins may also be an effective strategy in enhancing the activity of HDI based combination therapy against AML. Disclosures: Atajada: Novartis: Employment. Bhalla:Merck: Honoraria; Novartis: Honoraria, Research Funding.

scholarly journals IAP and HDAC inhibitors interact synergistically in myeloma cells through noncanonical NF-κB– and caspase-8–dependent mechanisms

2021 ◽  
Vol 5 (19) ◽  
pp. 3776-3788
Author(s):  
Liang Zhou ◽  
Yu Zhang ◽  
Mark B. Meads ◽  
Yun Dai ◽  
Yanxia Ning ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Caspase 8 ◽  
Apoptotic Pathway ◽  
Apoptosis Protein

Abstract Interactions between the inhibitor of apoptosis protein antagonist LCL161 and the histone deacetylase inhibitor panobinostat (LBH589) were examined in human multiple myeloma (MM) cells. LCL161 and panobinostat interacted synergistically to induce apoptosis in diverse MM cell lines, including those resistant to bortezomib (PS-R). Similar interactions were observed with other histone deacetylase inhibitors (MS-275) or inhibitors of apoptosis protein antagonists (birinapant). These events were associated with downregulation of the noncanonical (but not the canonical) NF-κB pathway and activation of the extrinsic, caspase-8–related apoptotic cascade. Coexposure of MM cells to LCL161/LBH589 induced TRAF3 upregulation and led to TRAF2 and NIK downregulation, diminished expression of BCL-XL, and induction of γH2A.X. Ectopic expression of TRAF2, NIK, or BCL-XL, or short hairpin RNA TRAF3 knock-down, significantly reduced LCL161/LBH589 lethality, as did ectopic expression of dominant-negative FADD. Stromal/microenvironmental factors failed to diminish LCL161/LBH589–induced cell death. The LCL161/LBH589 regimen significantly increased cell killing in primary CD138+ cells (N = 31) and was particularly effective in diminishing the primitive progenitor cell–enriched CD138–/19+/20+/27+ population (N = 23) but was nontoxic to normal CD34+ cells. Finally, combined LCL161/LBH589 treatment significantly increased survival compared with single-agent treatment in an immunocompetent 5TGM1 murine MM model. Together, these findings argue that LCL161 interacts synergistically with LBH589 in MM cells through a process involving inactivation of the noncanonical NF-κB pathway and activation of the extrinsic apoptotic pathway, upregulation of TRAF3, and downregulation of TRAF2/BCL-XL. Notably, this regimen overcomes various forms of resistance, is active against primary MM cells, and displays significant in vivo activity. This strategy warrants further consideration in MM.

scholarly journals Functional Interplay between Histone Demethylase and Deacetylase Enzymes

2006 ◽  
Vol 26 (17) ◽  
pp. 6395-6402 ◽  
Author(s):  
Min Gyu Lee ◽  
Christopher Wynder ◽  
Daniel A. Bochar ◽  
Mohamed-Ali Hakimi ◽  
Neil Cooch ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Hdac Inhibitors ◽  
Ectopic Expression ◽  
Histone Demethylase ◽  
Functional Connection ◽  
Histone Deacetylase 1 ◽  
In Vivo Analysis

ABSTRACT Histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents for the treatment of solid and hematological malignancies. The precise mechanism by which HDAC inhibitors mediate their effects on tumor cell growth, differentiation, and/or apoptosis is the subject of intense research. Previously we described a family of multiprotein complexes that contain histone deacetylase 1/2 (HDAC1/2) and the histone demethylase BHC110 (LSD1). Here we show that HDAC inhibitors diminish histone H3 lysine 4 (H3K4) demethylation by BHC110 in vitro. In vivo analysis revealed an increased H3K4 methylation concomitant with inhibition of nucleosomal deacetylation by HDAC inhibitors. Reconstitution of recombinant complexes revealed a functional connection between HDAC1 and BHC110 only when nucleosomal substrates were used. Importantly, while the enzymatic activity of BHC110 is required to achieve optimal deacetylation in vitro, in vivo analysis following ectopic expression of an enzymatically dead mutant of BHC110 (K661A) confirmed the functional cross talk between the demethylase and deacetylase enzymes. Our studies not only reveal an intimate link between the histone demethylase and deacetylase enzymes but also identify histone demethylation as a secondary target of HDAC inhibitors.

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