5-Aza-2’-deoxycytidine Induces Hepatoma Cell Apoptosis via Enhancing Methionine Adenosyltransferase 1A Expression and Inducing S-Adenosylmethionine Production

In hepatocellular cancer (HCC), lack of response to chemotherapy and radiation treatment can be caused bya loss of epigenetic modifications of cancer cells. Methionine adenosyltransferase 1A is inactivated in HCC andmay be stimulated by an epigenetic change involving promoter hypermethylation. Therefore, drugs releasingepigenetic repression have been proposed to reverse this process. We studied the effect of the demethylating reagent5-aza-2’-deoxycitidine (5-Aza-CdR) on MAT1A gene expression, DNA methylation and S-adenosylmethionine(SAMe) production in the HCC cell line Huh7. We found that MAT1A mRNA and protein expression wereactivated in Huh7 cells with the treatment of 5-Aza-CdR; the status of promoter hypermethylation was reversed.At the same time, MAT2A mRNA and protein expression was significantly reduced in Huh7 cells treated with5-Aza-CdR, while SAMe production was significantly induced. However, 5-Aza-CdR showed no effects onMAT2A methylation. Furthermore, 5-Aza-CdR inhibited the growth of Huh7 cells and induced apoptosis andthrough down-regulation of Bcl-2, up-regulation of Bax and caspase-3. Our observations suggest that 5-Aza-CdR exerts its anti-tumor effects in Huh7 cells through an epigenetic change involving increased expression ofthe methionine adenosyltransferase 1A gene and induction of S-adenosylmethionine production.