Methionine adenosyltransferase α2 sumoylation positively regulate Bcl-2 expression in human colon and liver cancer cells
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Maria Lauda Tomasi1,2, Minjung Ryoo1,2, Komal Ramani1,2, Ivan Tomasi3, Pasquale Giordano4, José M. Mato5, Shelly C. Lu1,2
1Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
2USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
3General Surgery Department, Rotherham Hospital, Rotherham S60 2UD, UK
4Colorectal Department, Barts Health, London E11 1NR, UK
5CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, 48160 Derio, Bizkaia, Spain
Shelly C. Lu, e-mail: firstname.lastname@example.org
Keywords: methionine adenosyltransferase α2, Bcl-2, ubiquitin-conjugating enzyme 9, sumoylation, colon cancer
Received: June 09, 2015 Accepted: September 15, 2015 Published: September 25, 2015
Ubiquitin-conjugating enzyme 9 (Ubc9) is required for sumoylation and inhibits apoptosis via Bcl-2 by unknown mechanism. Methionine adenosyltransferase 2A (MAT2A) encodes for MATα2, 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 MATα2 can regulate Bcl-2 expression at multiple levels. MATα2 binds to Bcl-2 promoter to activate its transcription. This effect is independent of SAMe as MATα2 catalytic mutant was also effective. MATα2 also directly interacts with Bcl-2 to enhance its protein stability. MATα2’s effect on Bcl-2 requires Ubc9 as MATα2’s stability is influenced by sumoylation at K340, K372 and K394. Overexpressing wild type (but not less stable MATα2 sumoylation mutants) protected from 5-fluorouracil-induced apoptosis in both colon and liver cancer cells. Colon cancer have higher levels of sumoylated MATα2, total MATα2, Ubc9 and Bcl-2 and higher MATα2 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 MATα2 protein, which in turn positively maintains Bcl-2 expression. These interactions feed forward to further enhance growth and survival of the cancer cell.
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