Methionine adenosyltransferase II β subunit gene expression provides a proliferative advantage in human hepatoma

Abstract

Background and Aims: Of the 2 genes (MATIA, MAT2A) encoding methionine adenosyltransferase, the enzyme that synthesizes S-adenosylmethionine, MAT1A, is expressed in liver, whereas MAT2A is expressed in extrahepatic tissues. In liver, MAT2A expression associates with growth, dedifferentiation, and cancer. Here, we identified the β subunit as a regulator of proliferation in human hepatoma cell lines. The β subunit has been cloned and shown to lower the Km of methionine adenosyltransferase II α2 (the MAT2A product) for methionine and to render the enzyme more susceptible to S-adenosylmethionine inhibition. Methods: Methionine adenosyltransferase II α2 and β subunit expression was analyzed in human and rat liver and hepatoma cell lines and their interaction studied in HuH7 cells. β Subunit expression was up- and down-regulated in human hepatoma cell lines and the effect on DNA synthesis determined. Results: We found that β subunit is expressed in rat extrahepatic tissues but not in normal liver. In human liver, β subunit expression associates with cirrhosis and hepatoma. β Subunit is expressed in most (HepG2, PLC, and Hep3B) but not all (HuH7) hepatoma cell lines. Transfection of β subunit reduced S-adenosylmethionine content and stimulated DNA synthesis in HuH7 cells, whereas down-regulation of β subunit expression diminished DNA synthesis in HepG2. The interaction between methionine adenosyltransferase II α2 and β subunit was demonstrated in HuH7 cells. Conclusions: Our findings indicate that β subunit associates with cirrhosis and cancer providing a proliferative advantage in hepatoma cells through its interaction with methionine adenosyltransferase II α2 and down-regulation of S-adenosylmethionine levels.