scholarly journals Histone Deacetylase Expressions in Hepatocellular Carcinoma and Functional Effects of Histone Deacetylase Inhibitors on Liver Cancer Cells In Vitro

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1587 ◽  
Author(s):  
Kim Freese ◽  
Tatjana Seitz ◽  
Peter Dietrich ◽  
Serene M.L. Lee ◽  
Wolfgang E. Thasler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Molecular Mechanisms ◽  
Trichostatin A ◽  
Class I ◽  
Common Mechanism ◽  
Promising Therapeutic Approach ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a leading cause for deaths worldwide. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy. However, most pharmacological HDACi unselectively block different HDAC classes and their molecular mechanisms of action are only incompletely understood. The aim of this study was to systematically analyze expressions of different HDAC classes in HCC cells and tissues and to functionally analyze the effect of the HDACi suberanilohydroxamic acid (SAHA) and trichostatin A (TSA) on the tumorigenicity of HCC cells. The gene expression of all HDAC classes was significantly increased in human HCC cell lines (Hep3B, HepG2, PLC, HuH7) compared to primary human hepatocytes (PHH). The analysis of HCC patient data showed the increased expression of several HDACs in HCC tissues compared to non-tumorous liver. However, there was no unified picture of regulation in three different HCC patient datasets and we observed a strong variation in the gene expression of different HDACs in tumorous as well as non-tumorous liver. Still, there was a strong correlation in the expression of HDAC class IIa (HDAC4, 5, 7, 9) as well as HDAC2 and 8 (class I) and HDAC10 (class IIb) and HDAC11 (class IV) in HCC tissues of individual patients. This might indicate a common mechanism of the regulation of these HDACs in HCC. The Cancer Genome Atlas (TCGA) dataset analysis revealed that HDAC4, HDAC7 and HDAC9 as well as HDAC class I members HDAC1 and HDAC2 is significantly correlated with patient survival. Furthermore, we observed that SAHA and TSA reduced the proliferation, clonogenicity and migratory potential of HCC cells. SAHA but not TSA induced features of senescence in HCC cells. Additionally, HDACi enhanced the efficacy of sorafenib in killing sorafenib-susceptible cells. Moreover, HDACi reestablished sorafenib sensitivity in resistant HCC cells. In summary, HDACs are significantly but differently increased in HCC, which may be exploited to develop more targeted therapeutic approaches. HDACi affect different facets of the tumorigenicity of HCC cells and appears to be a promising therapeutic approach alone or in combination with sorafenib.

scholarly journals Activation of MHC Class I, II, and CD40 Gene Expression by Histone Deacetylase Inhibitors

2000 ◽  
Vol 165 (12) ◽  
pp. 7017-7024 ◽  
Author(s):  
William J. Magner ◽  
A. Latif Kazim ◽  
Carleton Stewart ◽  
Michelle A. Romano ◽  
Geoffrey Catalano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Mhc Class I ◽  
Histone Deacetylase Inhibitors ◽  
Class I ◽  
Cd40 Gene

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 Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

2019 ◽  
Vol 93 (12) ◽  
Author(s):  
Bratati Saha ◽  
Robin J. Parks
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Trichostatin A ◽  
Human Adenovirus ◽  
Class I ◽  
Virus Yield ◽  
Hdac Activity ◽  
Viral Genes ◽  
Efficient Expression

ABSTRACTHuman adenovirus (HAdV) causes minor illnesses in most patients but can lead to severe disease and death in pediatric, geriatric, and immunocompromised individuals. No approved antiviral therapy currently exists for the treatment of these severe HAdV-induced diseases. In this study, we show that the pan-histone deacetylase (HDAC) inhibitor SAHA reduces HAdV-5 gene expression and DNA replication in tissue culture, ultimately decreasing virus yield from infected cells. Importantly, SAHA also reduced gene expression from more virulent and clinically relevant serotypes, including HAdV-4 and HAdV-7. In addition to SAHA, several other HDAC inhibitors (e.g., trichostatin A, apicidin, and panobinostat) also affected HAdV gene expression. We determined that loss of class I HDAC activity, mainly HDAC2, impairs efficient expression of viral genes, and that E1A physically interacts with HDAC2. Our results suggest that HDAC activity is necessary for HAdV replication, which may represent a novel pharmacological target in HAdV-induced disease.IMPORTANCEAlthough human adenovirus (HAdV) can cause severe diseases that can be fatal in some populations, there are no effective treatments to combat HAdV infection. In this study, we determined that the pan-histone deacetylase (HDAC) inhibitor SAHA has inhibitory activity against several clinically relevant serotypes of HAdV. This U.S. Food and Drug Administration-approved compound affects various stages of the virus lifecycle and reduces virus yield even at low concentrations. We further report that class I HDAC activity, particularly HDAC2, is required for efficient expression of viral genes during lytic infection. Investigation of the mechanism underlying SAHA-mediated suppression of HAdV gene expression and replication will enhance current knowledge of virus-cell interaction and may aid in the development of more effective antivirals with lower toxicity for the treatment of HAdV infections.

Combination Treatment of p53-Null HL-60 cells with Histone Deacetylase Inhibitors and Chlorambucil Augments Apoptosis and Increases BCL6 and p21 Gene Expression

2019 ◽  
Vol 12 (1) ◽  
pp. 72-81 ◽  
Author(s):  
Faith A.A. Kwa ◽  
Merrole F. Cole-Sinclair ◽  
Miroslav K. Kapuscinski
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Combination Treatment ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Control Cell ◽  
Leukemia Cell Line ◽  
Tetrazolium Salt ◽  
Treatment Type

Background:Treatment of hematological malignancies with conventional DNA-damaging drugs, such as chlorambucil (CLB), commonly results in p53-dependent chemo-resistance. Chromatin modifying agents, such as histone deacetylase inhibitors (HDACIs), sodium butyrate (NaBu) and trichostatin A (TSA), may reverse chemo-resistance by modulating the activity of chromatin remodeling enzymes and/or genes that control cell proliferation, differentiation and survival.Objective:This study examined the potential use of HDACIs and CLB combination therapies in an in vitro chemo-resistant leukemia model.Methods:The p53-null promyelocytic leukemia cell line, HL60, was used as an in vitro model of chemo-resistant leukemia. Drug cytotoxicity was determined by tetrazolium salt-based colorimetric assays and Annexin V/propidium iodide staining (flow cytometry). The level of mRNA expression of the chromatin modifying genes was measured by quantitative real-time PCR.Results:Micromolar concentrations of CLB combined with either NaBu or TSA triggered synergistic cytotoxic effects in HL-60 cells (p < 0.001). The effects of the combination treatments resulted in upregulated p21 gene expression (up to 59-fold; p<0.001) that preceded an increase in BCL6 gene expression (up to 20-fold; p < 0.001). Statistically significant but smaller magnitude changes (≤ 2-fold; p <0.05) were noted in the expression of other genes studied regardless of the treatment type.Conclusion:The combination treatment of p53-null HL-60 cells with DNA-damaging agent CLB and HDACIs NaBu and TSA triggered additive to synergistic effects on apoptosis and upregulated BCL6 and p21 expression. These findings reveal BCL6 and p21 as potential targets of chemo-resistance for the development of anti-leukemic drugs.

scholarly journals Inhibition of protein phosphatase 1 stimulates noncanonical ER stress eIF2α activation to enhance fisetin-induced chemosensitivity in HDAC inhibitor-resistant hepatocellular carcinoma cells

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 918 ◽  
Author(s):  
Liu ◽  
Yu-Chun ◽  
Chang ◽  
Kuo ◽  
Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Phosphatase ◽  
Cell Apoptosis ◽  
Histone Deacetylase Inhibitors ◽  
Molecular Mechanisms ◽  
Chemotherapeutic Agents ◽  
Protein Phosphatase 1 ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized that fisetin can act as an adjuvant therapy in cancer or drug-resistant cancer cells, and further investigated the molecular mechanisms underlying the development of drug-resistance in HCC cells. We found that fisetin effectively inhibited the cell viability of not only parental cells but also histone deacetylase inhibitors-resistant (HDACis-R) cells and enhanced the chemosensitivity of HCC cells. Interestingly, fisetin did not induce cell apoptosis through the activation of the endoplasmic reticulum (ER) stress sensor of protein kinase R (PKR)-like endoplasmic reticulum kinase, but rather through the non-canonical pathway of the protein phosphatase 1 (PP1)-mediated suppression of eIF2α phosphorylation. Moreover, fisetin-induced cell apoptosis was reversed by treatment with PP1 activator or eIF2α siRNA in HCC cells. Based on these observations, we suggest that PP1-eIF2α pathways are significantly involved in the effect of fisetin on HCC apoptosis. Thus, fisetin may act as a novel anticancer drug and new chemotherapy adjuvant which can improve the efficacy of chemotherapeutic agents and diminish their side-effects.

scholarly journals Improved development of mouse SCNT embryos by chlamydocin analogues, class I and IIa histone deacetylase inhibitors†

2021 ◽  
Author(s):  
Satoshi Kamimura ◽  
Kimiko Inoue ◽  
Eiji Mizutani ◽  
Jin-Moon Kim ◽  
Hiroki Inoue ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Class I ◽  
Cell Stage ◽  
Inhibitory Spectrum ◽  
Developmental Block

Abstract In mammalian cloning by somatic cell nuclear transfer (SCNT), treatment of reconstructed embryos with histone deacetylase (HDAC) inhibitors improves efficiency. So far, most of those used for SCNT are hydroxamic acid derivatives—such as trichostatin A—characterized by their broad inhibitory spectrum. Here, we examined whether mouse SCNT efficiency could be improved using chlamydocin analogues, a family of newly designed agents that specifically inhibit Class I and IIa HDACs. Development of SCNT-derived embryos in vitro and in vivo revealed that four out of five chlamydocin analogues tested could promote the development of cloned embryos. The highest pup rates (7.1 to 7.2%) were obtained with Ky-9, similar to those achieved with trichostatin A (7.2 to 7.3%). Thus, inhibition of Class I and/or IIa HDACs in SCNT-derived embryos is enough for significant improvements in full-term development. In mouse SCNT, the exposure of reconstructed oocytes to HDAC inhibitors is limited to 8–10 h because longer inhibition with Class I inhibitors causes a 2-cell developmental block. Therefore, we used Ky-29, with higher selectivity for Class IIa than Class I HDACs for longer treatment of SCNT-derived embryos. As expected, 24-h treatment with Ky-29 up to the 2-cell stage did not induce a developmental block, but the pup rate was not improved. This suggests that the 1-cell stage is a critical period for improving SCNT cloning using HDAC inhibitors. Thus, chlamydocin analogues appear promising for understanding and improving the epigenetic status of mammalian SCNT-derived embryos through their specific inhibitory effects on HDACs.

scholarly journals Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay

2011 ◽  
Vol 71 (3) ◽  
pp. 424-431 ◽  
Author(s):  
Aleksander M Grabiec ◽  
Olexandr Korchynskyi ◽  
Paul P Tak ◽  
Kris A Reedquist
Keyword(s):  
Rheumatoid Arthritis ◽  
Histone Deacetylase ◽  
Inflammatory Cytokine ◽  
Mrna Decay ◽  
Histone Deacetylase Inhibitors ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Trichostatin A ◽  
Binding Activity ◽  
Inflammatory Cytokine Production

BackgroundHistone deacetylase inhibitors (HDACi) display potent therapeutic efficacy in animal models of arthritis and suppress inflammatory cytokine production in rheumatoid arthritis (RA) synovial macrophages and tissue.ObjectivesTo determine the molecular mechanisms contributing to the suppressive effects of HDACi on RA synovial cell activation, using interleukin 6 (IL-6) regulation as a model.MethodsRA fibroblast-like synoviocytes (FLS) and healthy donor macrophages were treated with IL-1β, tumour necrosis factor (TNF)α, lipopolysaccharide or polyinosinic:polycytidylic acid (poly(I:C)) in the absence or presence of the HDACi trichostatin A (TSA) or ITF2357 (givinostat). IL-6 production and mRNA expression was measured by ELISA and quantitative PCR (qPCR), respectively. Protein acetylation and the activation of intracellular signalling pathways were assessed by immunoblotting. The DNA-binding activity of nuclear factor κB (NFκB) and activator protein 1 (AP-1) components was measured by ELISA-based assays.ResultsHDACi (0.25–1.0 μM) suppressed RA FLS IL-6 production induced by IL-1β, TNFα and Toll-like receptor ligands. Phosphorylation of mitogen-activated protein kinases and inhibitor of κBα (IκBα) following IL-1β stimulation were unaffected by HDACi, as were AP-1 composition and binding activity, and c-Jun induction. TSA induced a significant reduction in nuclear retention of NFκB in FLS 24 h after IL-1β stimulation, but this did not reduce NFκB transcriptional activity or correlate temporally with reductions in IL-6 mRNA accumulation. HDACi significantly reduced the stability of IL-6 mRNA in FLS and macrophages.ConclusionsOur study identifies a novel, shared molecular mechanism by which HDACi can disrupt inflammatory cytokine production in RA synovial cells, namely the promotion of mRNA decay, and suggests that targeting HDAC activity may be clinically useful in suppressing inflammation in RA.

Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors

2007 ◽  
Vol 409 (2) ◽  
pp. 581-589 ◽  
Author(s):  
Nagma Khan ◽  
Michael Jeffers ◽  
Sampath Kumar ◽  
Craig Hackett ◽  
Ferenc Boldog ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Specific Inhibitor ◽  
Class Ii ◽  
Class I ◽  
Regulation Of Transcription ◽  
Control Of Gene Expression ◽  
Inhibitor Treatment

The human HDAC (histone deacetylase) family, a well-validated anticancer target, plays a key role in the control of gene expression through regulation of transcription. While HDACs can be subdivided into three main classes, the class I, class II and class III HDACs (sirtuins), it is presently unclear whether inhibiting multiple HDACs using pan-HDAC inhibitors, or targeting specific isoforms that show aberrant levels in tumours, will prove more effective as an anticancer strategy in the clinic. To address the above issues, we have tested a number of clinically relevant HDACis (HDAC inhibitors) against a panel of rhHDAC (recombinant human HDAC) isoforms. Eight rhHDACs were expressed using a baculoviral system, and a Fluor de Lys™ (Biomol International) HDAC assay was optimized for each purified isoform. The potency and selectivity of ten HDACs on class I isoforms (rhHDAC1, rhHDAC2, rhHDAC3 and rhHDAC8) and class II HDAC isoforms (rhHDAC4, rhHDAC6, rhHDAC7 and rhHDAC9) was determined. MS-275 was HDAC1-selective, MGCD0103 was HDAC1- and HDAC2-selective, apicidin was HDAC2- and HDAC3-selective and valproic acid was a specific inhibitor of class I HDACs. The hydroxamic acid-derived compounds (trichostatin A, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat) were potent pan-HDAC inhibitors. The growth-inhibitory effect of the HDACis on HeLa cells showed that both pan-HDAC and class-I-specific inhibitors inhibited cell growth. The results also showed that both pan-HDAC and class-I-specific inhibitor treatment resulted in increased acetylation of histones, but only pan-HDAC inhibitor treatment resulted in increased tubulin acetylation, which is in agreement with their activity towards the HDAC6 isoform.

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