Genistein and Trichostatin A Induction of Estrogen Receptor Alpha Gene Expression, Apoptosis and Cell Growth Inhibition in Hepatocellular Carcinoma HepG 2 Cells

Abstract

Epigenetic changes such as DNA methylation and histone acetylation play important roles in determining gene<br /> expression. Hypermethylation of CpG islands of the promoter region of tumor suppressor genes can greatly influence<br /> carcinogenesis through transcriptional silencing. Acetylation of lysine in histone tails causes relaxation of chromatin,<br /> which facilitates gene transcription, while deacetylation is associated with condensed chromatin resulting in gene<br /> silencing. DNA demethylating agents such as genistein (GE) and histone deacetylase inhibitors (HDACIs) such as<br /> trichostatin A (TSA) may strongly reactivate silenced genes and exposure to these two agents in combination is reported<br /> to enhance estrogen receptor alpha (ERα) reactivation and induction of apoptosis. The present study was designed to<br /> evaluate the effect of these compounds on ERα gene expression, cell viability and apoptosis in hepatocellular carcinoma<br /> (HCC) Hep G2 cells. GE exerted biphasic effects; it stimulated cell growth at a low concentration (1 μM) but inhibitory<br /> influence was noted with high concentrations (10, 20 and 40 μM). In contrast, TSA demonstrated inhibitory effects on<br /> growth at all of concentrations tested. Furthermore, GE and GE/TSA significantly induced apoptosis at all concentrations,<br /> but TSA only after 72 h. GE induced ERα re-expression and this was maximal in combined treatment groups treated<br /> with GE/TSA for 72 h.<br /> <strong><span style="font-family: TimesNewRomanPS-BoldMT; font-size: small;"><span style="font-family: TimesNewRomanPS-BoldMT; font-size: small;">Discussion: </span></span></strong><span style="font-family: TimesNewRomanPSMT; font-size: small;" lang="JA"><span style="font-family: TimesNewRomanPSMT; font-size: small;" lang="JA">Our finding clearly indicates that GE and TSA have an inhibitory cell growth,</span></span><br /> induce apoptosis and reactivate the ERα gene expression. Conclusion: GE and TSA can significantly inhibit the growth<br /> of HCC cells and play a significant role in apoptosis and reactivation of ERα gene.