title: Methionine adenosyltransferase α2 sumoylation positively regulate Bcl-2 expression in human colon and liver cancer cells.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Maria Lauda
authors.initials: ML
authors.lastname: Tomasi
authors.affiliation: Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Minjung
authors.initials: M
authors.lastname: Ryoo
authors.affiliation: Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Komal
authors.initials: K
authors.lastname: Ramani
authors.affiliation: General Surgery Department, Rotherham Hospital, Rotherham S60 2UD, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tomasi
authors.affiliation: Colorectal Department, Barts Health, London E11 1NR, UK.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Giordano
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008716:Methionine Adenosyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000494:pharmacology; D058207:Sumoylation / Q000187:drug effects; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012436:S-Adenosylmethionine; D044763:Ubiquitin-Conjugating Enzymes; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: Bcl-2; colon cancer; methionine adenosyltransferase α2; sumoylation; ubiquitin-conjugating enzyme 9