MAT2a, MAT2b, HIF-1 alpha: Roles in Liver Cancer and DNA methylation

Methionine Adenosyltransferase II alpha, also known as MAT2a, is a catalytic subunit of methionine adenosyltransferase (MAT) and essential enzyme for the catalysis of the principle biological methyl donor, S-adenosylmethionine (SAM) from methionine and ATP. MAT2a's heterotetramer structure is composed of 2 catalytic alpha subunits (alpha and alpha’)¹. During development in the adult human liver, MAT2a and its gene products are progressively replaced by MAT1a during fetal liver development². Increased growth and malignant degenerations has been observed in hepatocytes expressing increased levels of MAT2a and MAT2b². It has been frequently observed in malignant liver transformation, that the expression of MAT1a is switched to MAT2a, which is believed to be an important factor in facilitating liver cancer progression³.

Recent studies have been conducted to investigate the potential interaction between MAT2a and HIF-1a as a mechanism being responsible for the change in genomic DNA methylation patterns found in liver cancer under hypoxic conditions. MAT2a was identified as a novel target gene that is transcriptionally regulated by HIF-1a. This provided the evidence needed to support that genomic DNA methylation is regulated by activation of HIF-1a and the up-regulation of MAT2a in hepatoma cells under hypoxic conditions³. Western blot and luciferase analysis in this study revealed a positive correlation between HIF-1a and MAT2a promoter activity expression in Hep3B cells after Hypoxic treatment. The use of siRNA to knockdown HIF-1a was shown to prevent the expression of MAT2a.  Furthermore, ChIP analysis revealed a significant increase in the binding of HIF-1a to the MAT2a promoter within hypoxic Hep3B cells³. The results from this study suggest that genomic DNA methylation is facilitated by the activated expression of MAT2a through HIF-1a under hypoxic conditions, due to the increase of MAT II activity and decrease of SAM production.

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References:

1. Wang Q, Liu Q, Liu Z, Qian Q, Sun Q and Pan D. Inhibition of hepatocellular carcinoma MAT2A and MAT2beta gene expressions by single and dual small interfering RNA. Journal of Experimental & Clinical Cancer Research 2008. 27:72. [PMID: 19025580]

2. Chen H, Xia M, Lin M, Yang H, Kuhlenkamp J, Li T, Sodir NM, Chen YH, Josef-Lenz H, Laird P, Clarke S, Mato J, and Lu S.  Role of Methionine Adenosyltransferase 2A and S—adenosylmethionin in Mitogen-Induced Growth of Human Colon Cancer Cells. Gastroenterology 2007; 133:207-218. [PMID: 17631143]

3. Liu Q, Liu L, Zhao Y, Zhang J, Wang D, Chen J, He Y, Wu J, Zhang Z, and Liu Z. Hypoxia Induces Genomic DNA Demethylation through the activation of HIF-1a and Transcriptional Upregulation of MAT2A in Heptoma Cells. Molecular Cancer Therapeutics 2011;10:1113-1123. [PMID: 21460102]