Epigenetics is the study of heritable modifications in gene expression and reversible forms of gene regulation. Recent in-vitro works have indicated that epigenetics plays a significant role in many types of human cancers e. g. hepatocellular carcinoma (HCC). Diverse cellular functions are regulated by histone acetylation and deacetylation. Histone deacetylases (HDACs) and histone acetylases (HATs) are enzymes involved in chromatin remodeling histone deacetylation and acetylation respectively. Aberrant protein acetylation, particularly histone deacetylation, has been reported in a broad range of human cancer types. Epigenetic modification by inhibiting HDAC activity is an emerging approach in cancer treatment. HDACIs play their apoptotic roles through multiple mechanisms such as extrinsic/cytoplasmic and intrinsic/mitochondrial molecular mechanisms. Here, we summarize the major classes of HDACs and epigenetic compounds, HDACIs, and also their molecular mechanisms in HCC including intrinsic and extrinsic apoptotic pathways. An online search of different sources including PubMed, ISI, and Scopus was achieved to find suitable data on mechanisms and pathways of HDACs and HDACIs in HCC. The result demonstrated that the dysregulation of HDACs because of histone deacetylation induces HCC. The histone deacetylation can be reversed by HDACIs resulting in apoptosis induction. In conclusion, because histone deacetylation is a potentially reversible change, epigenetic histone modification represents new opportunities for cancer management by reactivation of gene silencing. The inhibition of HDACs by GDACIs can effectively induce apoptosis and suppress cancer cell proliferation. These compounds can engage both intrinsic and extrinsic apoptotic pathways.

Background: Histone deacetylase inhibitors (HDACIs) are novel anticancer agents that induce cell death and cycle arrest. Several studies reported that HDACIs induce apoptosis via two well-defined intrinsic/mitochondrial and death receptor pathways. In addition to HDACIs, DNA methyltransferase inhibitors effectively revert the promoter hypermethylation of tumor suppressor genes and apoptosis induction. The current study aimed to investigate the effect of sodium butyrate and epigallocatechin-3-gallate (EGCG) on the genes expression of the intrinsic pathway (BAX, BAK, APAF1, Bcl-2, and Bcl-xL), p21, and p53 on PA-TU-8902, CFPAC-1, and CAPAN-1 human pancreatic cancer cell lines. Materials and Methods: The PA-TU-8902, CFPAC-1, and CAPAN-1 cells were treated with sodium butyrate and EGCG. To determine cell viability, cell apoptosis, and the relative gene expression level, the 3-(4, 4-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and real-time quantitative reverse transcription polymerase chain reaction were done, respectively. Results: Both compounds changed the expression levels of the mentioned genes in a p53-dependent and-independent manner, which induced cell apoptosis and inhibited cell growth in all three cell lines. Conclusion: We indicated that sodium butyrate and EGCG could induce apoptosis in human pancreatic cancer cell lines.

Background: The aberrant and altered patterns of gene expression play an important role in the biology of cancer and tumorigenesis. DNA methylation and histone deacetylation are the most studied epigenetic mechanisms. Histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA) and trichostatin A (TSA) are a group of anticancer compounds for the treatment of solid and hematological cancers. Previously, we reported the effect of two HDACIs, valproic acid (VPA) and TSA, on colon cancer and hepatocellular carcinoma (HCC), respectively. The aim of the current in vitro study is to investigate the effects of TSA on the intrinsic apoptotic pathway, p21/Waf1/Cip1 (p21), p53, and histone deacetylases (HDACs) 1, 2 and 3 in human neuroblastoma LAN-1, glioblastoma GBM-29, HCC SMMC7721, and colon cancer COLO 201 cell lines. Materials and methods: In this lab-trial study, all three cell lines were seeded at the density of 3 × 105 cells per well and incubated for 24 hours. Then, the cells were treated with TSA based on IC50 values for 24 hours except in the control groups,the control cells were treated with the equal amounts of the DMSO solvent. Subsequently, cell viability, cell apoptosis and gene expression were determined by three techniques including MTT assay, flow cytometry assay, and qRT-PCR. Results: The result of qRT-PCR indicated that TSA could increase the expression levels of Bid, BimEL, Noxa, p21, and p53 genes and decrease those of Bcl-xL, RIP, Mcl-1, XIAP, HDACs 1, 2 and 3 significantly (P < 0. 0001) by which it inhibited cell growth and induced significant cell apoptosis in LAN-1, GBM-29, SMMC7721, and COLO 201 cell lines (p value<0. 001). Conclusion: TSA can affect cell apoptotic via the intrinsic apoptotic pathway in LAN-1, GBM-29, SMMC7721, and COLO 201 cell lines.

Background: Histone acetylation and deacetylation play an important role in transcription and gene expression. The acetylation status of histones and non-histone proteins is determined by histone acetyl-transferases (HATs) and histone deacetylases (HDACs). Histone deacetylase inhibitors (HDACIs) induce various molecular and extracellular effects, leading to potent anti-cancer activities. The current study was designed to investigate the effect of valproic acid )VPA( on extrinsic and intrinsic apoptotic pathways, cell viability, and apoptosis in hepatocellular carcinoma PLC/PRF5 cell line. Materials and Methods: The hepatocellular carcinoma PLC/PRF5 was cultured. When cells approximately became 80% confluent, 3×105 cells were seeded into 96 and 24‑ well plates. After 24 h, the medium was replaced with the medium contains VPA (except control groups which were treated with DMSO). After 24, 48, and 72 h, to determine cell viability, cell apoptosis and gene expression, MTT assay, flow cytometry and Real-time quantitative RT-PCR (qRT-PCR) were done respectively. Results: VPA inhibited cell viability, induced apoptosis, decreased Bcl-2, and Bcl-xL and increased DR4, DR5, FAS, FAS-L, TRAIL, BAX, BAK and APAF1 significantly. Conclusion: It seems that VPA can play its role through intrinsic and extrinsic apoptotic pathways in hepatocellular carcinoma PLC/PRF5 cell line.

Epigenetic alterations, including DNA acetylation, hypermethylation and hypomethylation, and the associated transcriptional changes of the affected genes are central to the evolution and progression of various human cancers, including pancreatic cancer. Cancer-associated epigenetic alterations are attractive therapeutic targets because such epigenetic alterations, unlike genetic changes, are potentially reversible. Several drugs that target epigenetic alterations, including inhibitors of histone deacetylase (HDAC) and DNA methyltransferase (DNMT), are currently approved for treatment of hematological malignancies and are available for clinical investigation in solid tumors. Histone deacetylases (HDACs) is well known to be associated with tumorigenesis through epigenetic regulation. HDACs comprise an ancient family of enzymes that play crucial roles in numerous biological processes and HDACs are found to be over expressed in many tumor types. Its inhibitors (HDACIs) induce differentiation and apoptosis of tumor cells. In addition, the activity of heat shock proteins (Hsps) can be regulated by HDACs. Hsps exist in many types of cells and these proteins can prevent aggregation and formation of toxic inclusion. Hsps are major molecular chaperones in prokaryotic and eukaryotic cells. This review summarizes mechanisms of histone deacetylase inhibitors action on Hsps and will describe the regulation of major cellular chaperones and heat shock factors by HDACmediated deacetylation.

Background: Valproic acid (VPA) and carbamazepine (CBZ), two widely used antiepileptic drugs, have recently been found to inhibit histone deacetylases (HDAC). HDAC inhibitors (HDACIs) have various effects on cancer cells.Objectives: The aim of this study was to compare the anticancer activity of these drugs on SW480 colon cancer cell lines.Methods: In the present experimental study, implemented during 2014 - 2015 in Iran, after incubation of 8×106 cells into 96-well plates with 5, 500 cells/well, the tested drugs were added, and cytotoxic effects were assessed by MTT. Moreover, after incubation of 8106 cells in 75 cm2 flasks to obtain -catenin levels and 106 cells in a six-well plate to obtain vascular endothelial growth factor (VEGF) levels, these levels were estimated using enzyme-linked immunosorbent assay (ELISA) analysis.Results: Through MTT assay, we found that the inhibitory concentration of 50% (IC50) values for VPA and CBZ were 2.5 mM and 5mM, respectively in comparison to controls in terms of total concentration and times evaluated (P<0.0001). We also found that treatments with these drugs decreased levels of b-catenin (P<0.0001) and VEGF (P<0.0001) significantly more than controls.Conclusions: VPA and CBZ treatments caused a decrease in b-Catenin and VEGF levels in SW480 colon cancer cell lines. These results suggest that CBZ can be considered a potential antitumor drug with potencies different from VPA.

Aim: The current study aimed to investigate the effect of valproic acid (VPA) on SOCS-1, SOCS-2, SOCS-3, SOCS-5, SOCS6, and SOCS-7 gene expression and cell growth inhibition in colon carcinoma IS1, IS2, and IS3 cell lines. Background: Cancer is a process induced by the accumulation of epigenetic alterations such as DNA methylation and histone deacetylation. The DNA methylation and histone deacetylation of tumor suppressor genes (TSGs) have been shown in various cancers. The methylation and deacetylation of suppressors of the cytokine signaling (SOCS) family, as TSGs, have been demonstrated in numerous cancers. Histone deacetylase inhibitors (HDACIs) have emerged as accessory therapeutic agents for human cancers. Methods: IS1, IS2, and IS3 cells were cultured and treated with VPA. To determine cell viability, cell apoptosis, and the relative gene expression level, MTT assay, flow cytometry assay, and qRT-PCR, respectively, were performed. A database was established with the SPSS 16. 0 software package (SPSS Inc., Chicago, Illinois, USA) for analysis. Data was acquired from three tests and is shown as means ± standard deviations. A significant difference was considered as p < 0. 05. Results VPA changed the expression levels of the SOCS-1, SOCS-2, SOCS-3, SOCS-5, SOCS6, and SOCS-7 genes, by which cell apoptosis was induced and cell growth inhibited in all three cell lines (p < 0. 0001). Conclusion: VPA can induce apoptosis through reactivation of SOCS-1, SOCS-2, SOCS-3, SOCS-5, SOCS6, and SOCS-7 gene expression.

Background and purpose: In mammalian cells, several distinct surveillance systems, named cell cycle checkpoints, can interrupt normal cell-cycle progression. The cyclin-dependent kinases are negatively regulated by proteins of cyclin-dependent kinases inhibitors comprising INK4 and Cip/Kip families. Histone deacetylation induced by histone deacetylases (HDACs) inactivates the INK4 and Cip/Kip families lead to cancer induction. HDAC inhibitors (HDACIs) have been indicated to be potent inducers of differentiation, growth arrest, and apoptotic induction. Vorinostat (suberoylanilide hydroxamic acid, SAHA), as an HDACI, is reported to be useful in various cancers. Previously, we reported the effect of trichostatin A on hepatocellular carcinoma and also vorinostat on colon cancer cell lines. The current study was aimed to investigate the effect of vorinostat on p16INK4a, p14ARF, p15INK4b, and class I HDACs 1, 2, and 3 gene expression, cell growth inhibition, and apoptosis induction in pancreatic cancer AsPC-1 and hepatocellular carcinoma LCL-PI 11 cell lines. Experimental approach: The AsPC-1 and LCL-PI 11 cell lines were cultured and treated with vorinostat. To determine, viability, apoptosis, and the relative expression level of p16INK4a, p14ARF, p15INK4b, class I HDACs 1, 2, and 3 genes, MTT assay, cell apoptosis assay, and RT-qPCR were performed, respectively. Findings/Results: Vorinostat significantly inhibited cell growth, induced apoptosis, increased p16INK4a, p14ARF, p15INK4b, and decreased class I HDACs 1, 2, and 3 gene expression. Conclusion and implications: Vorinostat can reactivate the INK4 family through inhibition of class I HDACs 1, 2, and 3 genes activity.

Aim: The current study investigated the effect of trichostatin A (TSA) on mitochondrial/intrinsic [pro-(Bax, Bak, and Bim) and anti-(Bcl-2, Bcl-xL, and Mcl-1) apoptotic genes] and cytoplasmic/extrinsic (DR4, DR5, FAS, FAS-L, and TRAIL genes) pathways, histone deacetylase 1, 2, and 3, p53, p73, cell viability, and apoptosis in hepatocellular carcinoma (HCC) HCCLM3, MHCC97H, and MHCC97L cell lines. Background: Modulation of the acetylation status of histones, histones modification, plays an important role in regulating gene transcription and expression. Histone deacetylation controlled by histone deacetylases (HDACs) leads to gene downregulation. Histone deacetylase inhibitors (HDACIs) are an emerging class of therapeutics with potential anticancer effects. They can induce apoptosis by activating both extrinsic and intrinsic apoptotic pathways Methods: HCCLM3, MHCC97H, and MHCC97L cells were cultured and treated with TSA. To determine viability, apoptosis, and the relative expression level of the mentioned genes, MTT assay, cell apoptosis assay, and qRT-PCR, respectively, were conducted. Results: TSA up-regulated Bax, Bak, Bim, DR4, DR5, FAS, FAS-L, TRAIL, p53, and p73 and down-regulated Bcl-2, Bcl-xL, Mcl1, histone deacetylases 1, 2, and 3 significantly, resulting in apoptosis induction. Maximal and minimal apoptosis was seen in the MHCC97H and HCCLM3 cell lines (93. 94% and 39. 68%, respectively) after 24 and 48 h. Therefore, the MHCC97H cell line was more sensitive to TSA. Conclusion: The current findings demonstrated that the HDAC inhibitor TSA can induce apoptosis and inhibit cell growth through both mitochondrial/intrinsic and cytoplasmic/extrinsic apoptotic pathways in hepatocellular carcinoma HCCLM3, MHCC97H, and MHCC97L cell lines.