Role of transcriptional and posttranscriptional regulation of methionine adenosyltransferases in liver cancer progression

Abstract

Down-regulation of the liver-specific MAT1A gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and up-regulation of widely expressed MAT2A, encoding MATII isozyme, known as MAT1A:MAT2A switch, occurs in hepatocellular carcinoma (HCC). Here we found Mat1A:Mat2A switch and low SAM levels, associated with CpG hypermethylation and histone H4 deacetylation of Mat1A promoter, and prevalent CpG hypomethylation and histone H4 acetylation in Mat2A promoter of fast-growing HCC of F344 rats, genetically susceptible to hepatocarcinogenesis. In HCC of genetically resistant BN rats, very low changes in the Mat1A:Mat2A ratio, CpG methylation, and histone H4 acetylation occurred. The highest MAT1A promoter hypermethylation and MAT2A promoter hypomethylation occurred in human HCC with poorer prognosis. Furthermore, levels of AUF1 protein, which destabilizes MAT1A messenger RNA (mRNA), Mat1A-AUF1 ribonucleoprotein, HuR protein, which stabilizes MAT2A mRNA, and Mat2A-HuR ribonucleoprotein sharply increased in F344 and human HCC, and underwent low/no increase in BN HCC. In human HCC, Mat1A:MAT2A expression and MATI/ III:MATII activity ratios correlated negatively with cell proliferation and genomic instability, and positively with apoptosis and DNA methylation. Noticeably, the MATI/III:MATII ratio strongly predicted patient survival length. Forced MAT1A overexpression in HepG2 and HuH7 cells led to a rise in the SAM level, decreased cell proliferation, increased apoptosis, down-regulation of Cyclin D1, E2F1, IKK, NF-jB, and antiapoptotic BCL2 and XIAP genes, and up-regulation of BAX and BAK proapoptotic genes. In conclusion, we found for the first time a post-transcriptional regulation of MAT1A and MAT2A by AUF1 and HuR in HCC. Low MATI/III:MATII ratio is a prognostic marker that contributes to determine a phenotype susceptible to HCC and patients' survival. Conclusion: Interference with cell cycle progression and I-kappa B kinase (IKK)/nuclear factor kappa B (NF-jB) signaling contributes to the antiproliferative and proapoptotic effect of high SAM levels in HCC. (HEPATOLOGY 2012;56:165-175)

MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma

“…In both animal models and human HCC, decreased MAT1A expression correlates with more aggressive disease and worse prognosis (21). Consistent with an important role of MAT1A in HCC pathogenesis, mice deficient in Mat1a develop spontaneous HCC (7).…”

“…MAT1A is predominantly expressed in normal liver, and it is often silenced in human HCC (3,4,20,21). In both animal models and human HCC, decreased MAT1A expression correlates with more aggressive disease and worse prognosis (21).…”

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

“…It has been found that Mat1A:Mat2A switch and low SAM levels, associated with CpG hypermethylation of Mat1A promoter, and prevalent CpG hypomethylation in Mat2A promoter of fast growing HCC (Frau et al, 2012). Forced MAT1A overexpression in HepG2 and Huh7 cells led to rise in SAMe level, decreased cell proliferation, increased apoptosis (Li et al, 2010;Frau et al, 2012).…”

“…We found that 5-Aza-CdR inhibited the growth of Huh7 cells and induced apoptosis in Huh7 cells. Furthermore, We investigated 5-Aza-CdR induced apoptosis in Huh7 cells through down-regulation of Bcl-2, up-regulation of Bax and caspase-3, we inferred increased SAMe production by 5-Aza-CdR caused the result (Frau et al, 2012).…”

“…The gDNA was subjected to sodium bisulfite treatment using an EpiTect Bisulfite Kit (Qiagen, Germany). Fifty ng of bisulfitemodified DNA was subjected to methylationAsian Pacific Journal of Cancer Prevention, Vol 14, 2013 6435 DOI:http://dx.doi.org/10.7314/APJCP.2013.14.11.6433 5-Aza-2'- Methylated and unmethylated DNA primer pairs were designed as described previously (Wang et al, 2011;Frau et al, 2012;Zhang et al, 2013). Detailed sequences are listed in Table 1.…”