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 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.

A 100-ns MD simulation of the apo-protein and compound A protein complex was carried out using RMSD and RMSF evaluations to investigate the stability of the tested complex with regards to the HDAC-2 target site. The apoprotein (C𝛼) showed a significant RMSD value of 0.90 Å throughout the simulation period with no major fluctuation, showing the conformational stability of the apo-protein structure. In addition, the compound A/protein complex displayed stability during the simulation period with an RMSD value of 1.6 Å, suggesting a low chance of compound escape from the target pocket with no fluctuation.

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.