Role of promoter methylation in increased methionine adenosyltransferase 2A expression in human liver cancer

Methionine adenosyltransferase (MAT), an essential enzyme that catalyzes th e formation of S-adenosylmethionine (SAM), is encoded by two genes, MAT1A ( liver-specific) and MAT2A (non-liver-specific). We showed a switch from MAT 1A to MAT2A expression in human liver cancer, which facilitates cancer cell growth. The present work examined the role of methylation in MAT2A transcr iptional regulation. We found that the human MAT2A promoter is hypomethylat ed in hepatocellular carcinoma, in which the gene is upregulated transcript ionally, but hypermethylated in normal liver, in which the gene is minimall y expressed. Luciferase activities driven by in vitro methylated MAT2A prom oter constructs were 75-95% lower than activities driven by unmethylated co nstructs. SAM treatment of Hep G2 cells reduced MAT2A endogenous expression by 75%, hypermethylated the MAT2A promoter, and reduced luciferase activit ies driven by MAT2A promoter constructs by 65-75% while not affecting MAT1A 's promoter activity. Treatment of adult rat and human hepatocytes with tri chostatin A, an inhibitor of histone deacetylase, upregulated MAT2A express ion by more than fourfold. Collectively, these results suggest that MAT2A e xpression is regulated by promoter methylation and histone acetylation.