Abstract
In hepatocellular cancer (HCC), lack of response to chemotherapy and radiation treatment can be caused by a loss of epigenetic modifications of cancer cells. Methionine adenosyltransferase 1A is inactivated in HCC and may be stimulated by an epigenetic change involving promoter hypermethylation. Therefore, drugs releasing epigenetic repression have been proposed to reverse this process. We studied the effect of the demethylating reagent 5-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 were activated 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 with 5-Aza-CdR, while SAMe production was significantly induced. However, 5-Aza-CdR showed no effects on MAT2A methylation. Furthermore, 5-Aza-CdR inhibited the growth of Huh7 cells and induced apoptosis and through 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 of the methionine adenosyltransferase 1A gene and induction of S-adenosylmethionine production.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world; there is no drug intervention effective for the treatment of HCC (Huang et al, 2011; Villanueva et al, 2011)
The results revealed that the effect of 5-Aza-CdR on MAT1A and MAT2A protein expression varied in different 5-Aza-CdR concentration, and kept a consistency with mRNA expression (Figure 1)
DNA methylation normally occurs at the cytosine residues within CpG dinucleotides through action of DNA methyltransferases (DNMTs)
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world; there is no drug intervention effective for the treatment of HCC (Huang et al, 2011; Villanueva et al, 2011). Exogenous SAMe inhibits the growth of hepatoma cells and prevents development of HCC (Cai et al, 1998; Martínez-Chantar et al, 2006; Lu et al, 2009). 5-Aza-CdR can inhibit hepatocellular carcinoma cells growth by inhibiting the telomerase activity and inducing p16 expression (Liu et al, 2001; Tao et al, 2012). We investigated the molecular mechanism underlying the effects of 5-aza-2’-deoxycytidine on MAT1A: MAT2A expression and SAMe production, we explored the effect of 5-Aza-CdR on apoptosis pathway in the Huh cell line. Our results demonstrated 5-aza-2’-deoxycytidine can reactivate MAT1A and inhibit MAT2A expression, induce S-Adenosylmethionine production of human hepatoma Huh cells through reversing the hypermethylation of Mat1A promoter, and it induced apoptosis through downregulation of Bcl-2, up-regulation of Bax and caspase-3 in Huh cells
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