AIMS:A switch in gene expression from MAT1A to MAT2A was found in liver cancer, suggesting that MAT2A plays an important role in facilitating cancer growth. MAT2A is an interesting target for antineoplastic therapy. The molecular mechanisms of silencing MAT2A by RNA interference inhibited cell growth and induced apoptosis in hepatoma cells was studied. METHODS:We investigated the effects of MAT2A on S-adenosyl-methionine (SAM) production, cell growth and apoptotic cell death in hepatoma cell lines (Bel-7402, HepG2, and Hep3B) using an RNA interference approach. RESULTS:The treatment of three hepatoma cell lines with small interfering RNA (siRNA) targeting to the MAT2A gene resulted in reducing the MAT II activity, facilitating SAM production, increasing SAM : SAH ratio, inhibiting cell growth and inducing cell apoptosis in hepatoma cells. In addition, silencing MAT2A gene resulted in the stimulation of MAT1A mRNA production, which was blocked by 3-deazaadenosine and l-ethionine, but not d-ethionine, suggesting that such effect was specific and mediated by upregulation of SAM level and SAM : S-adenosylethionine (SAH) ratio. CONCLUSION:Silencing MAT2A by sequence-specific small interfering RNA caused a switch of MAT gene expression from MAT2A to MAT1A, which led the content of SAM to change to a higher steady-state level that resulted in the inhibition of cell growth and the induction of apoptotic cell death in human hepatoma cells. These results also suggested that MAT2A may hold potential as a new target for liver cancer gene therapy.