Effect of Genistein in Comparison with Trichostatin A on Reactivation of DNMTs Genes in Hepatocellular Carcinoma

Abstract

Background and Aims: DNA methylation and histone modification are epigenetic modifications essential for normal function of mammalian cells. The processes are mediated by biochemical interactions between DNA methyltransferases (DNMTs) and histone deacetylases. Promoter hypermethylation and deacetylation of tumor suppressor genes play major roles in cancer induction, through transcriptional silencing of these genes. DNA hypermethylation is carried out by a family of DNMTs including DNMT1, DNMT3a and DNMT3b. In hepatocellular carcinoma, a significant positive correlation between over-expression of these genes and cancer induction has been reported. The DNA demethylating agent genistein (GE) has been demonstrated to reduce different cancers. Previously, we reported that GE can induce apoptosis and inhibit proliferation in hepatocellular carcinoma PLC/PRF5 and HepG2 cell lines. Besides, histone deacetylase inhibitors, such as trichostatin A (TSA), were successfully used to inhibit cancer cell growth. The present study was designed to assess the effect of GE in comparison with TSA on DNMT1, DNMT3a and DNMT3b gene expression, cell growth inhibition and apoptosis induction in the HepG2 cell line.Methods: Cells were seeded and treated with various doses of GE and TSA. The MTT assay, flow cytometry assay, and real-time RT-PCR were used to determine viability, apoptosis, and DNMT1, DNMT3a and DNMT3b gene expression respectively.Results: Both agents inhibited cell growth, induced apoptosis and reactivated DNMT1, DNMT3a and DNMT3b gene expression. Furthermore, TSA demonstrated a significantly greater apoptotic effect than the other agent, whereas GE improved gene expression more significantly than TSA.Conclusions: Our findings suggest that GE and TSA can significantly inhibit cell growth, induce apoptosis and restore DNMT1, DNMT3a and DNMT3b gene reactivation.

Survival analysis of genome-wide profiles coupled with Connectivity Map database mining to identify potential therapeutic targets for cholangiocarcinoma

“…Trichostatin A induces hyperacetylation of the core histone followed by structural modulation of chromatin, and finally causes the promotion of selective gene transcription and the suppression of tumor growth by reversibly inhibiting deacetylases. Currently, trichostatin A has been used in the treatment of laryngeal cancer and as a novel biomarker for nasopharyngeal carcinoma, and is also used to prevent the side effects of cisplatin in the treatment of cancer ( 38 ). It may have positive effects on CCA treatment.…”

Investigation of the effect of 5-Aza-2′-deoxycytidine on p15INK4, p16INK4, p18INK4, and p19INK4 genes expression, cell growth inhibition, and apoptosis induction in hepatocellular carcinoma PLC/PRF/5 cell line

“…Previously, we reported the effect of DNMT inhibitors 5-Aza-CdR and GE in HCC. [ 12 13 ] In the present study, we report that 5-Aza-CdR can inhibit PLC/PRF cell and induce apoptosis by epigenetic reactivation of p15INK4, p16INK4, p18INK4, and p19INK4 genes. Similarly, a regulatory link has been reported between DNMT downregulation and cell cycle regulator p21 WAF1 protein upregulation.…”

“…[ 11 ] Previously, we reported the effect of DNA demethylating agent 5-Aza-CdR and genistein (GE) on DNMTs in HCC. [ 12 13 ] The aim of the present study was to evaluate the effect of 5-Aza-CdR on p15INK4, p16INK4, p18INK4, and p19INK4 genes expression, cell growth inhibition, and apoptosis induction in HCC PLC/PRF/5 cell line.…”

Comparative proteomic analysis uncovers potential biomarkers involved in the anticancer effect of Scutellarein in human gastric cancer cells

“…DNA hypermethylation is carried out by a family of DNMTs including DNMT3A. In hepatocellular carcinoma, a positive correlation between the overexpression of these genes and cancer induction has been reported to be significant (41). DNMT3A protein expression was depleted in AGS cells treated with SCU, and functional analysis indicated its role in the apoptotic process by GO.…”