Ubiquitin-conjugating enzyme 9 (Ubc9) is required for sumoylation and inhibits apoptosis via Bcl-2 by unknown mechanism. Methionine adenosyltransferase 2A (MAT2A) encodes for MATalpha2, the catalytic subunit of the MATII isoenzyme that synthesizes S-adenosylmethionine (SAMe). Ubc9, Bcl-2 and MAT2A expression are up-regulated in several malignancies. Exogenous SAMe decreases Ubc9 and MAT2A expression and is pro-apoptotic in liver and colon cancer cells. Here we investigated whether there is interplay between Ubc9, MAT2A and Bcl-2. We used human colon and liver cancer cell lines RKO and HepG2, respectively, and confirmed key finding in colon cancer specimens. We found MATalpha2 can regulate Bcl-2 expression at multiple levels. MATalpha2 binds to Bcl-2 promoter to activate its transcription. This effect is independent of SAMe as MATalpha2 catalytic mutant was also effective. MATalpha2 also directly interacts with Bcl-2 to enhance its protein stability. MATalpha2's effect on Bcl-2 requires Ubc9 as MATalpha2's stability is influenced by sumoylation at K340, K372 and K394. Overexpressing wild type (but not less stable MATalpha2 sumoylation mutants) protected from 5-fluorouracil-induced apoptosis in both colon and liver cancer cells. Colon cancer have higher levels of sumoylated MATalpha2, total MATalpha2, Ubc9 and Bcl-2 and higher MATalpha2 binding to the Bcl-2 P2 promoter. Taken together, Ubc9's protective effect on apoptosis may be mediated at least in part by sumoylating and stabilizing MATalpha2 protein, which in turn positively maintains Bcl-2 expression. These interactions feed forward to further enhance growth and survival of the cancer cell.