title: Proteomic analysis of human hepatoma cells expressing methionine adenosyltransferase I/III: Characterization of DDX3X as a target of S-adenosylmethionine.
abstract: Methionine adenosyltransferase I/III (MATI/III) synthesizes S-adenosylmethionine (SAM) in quiescent hepatocytes. Its activity is compromised in most liver diseases including liver cancer. Since SAM is a driver of hepatocytes fate we have studied the effect of re-expressing MAT1A in hepatoma Huh7 cells using proteomics. MAT1A expression leads to SAM levels close to those found in quiescent hepatocytes and induced apoptosis. Normalization of intracellular SAM induced alteration of 128 proteins identified by 2D-DIGE and gel-free methods, accounting for deregulation of central cellular functions including apoptosis, cell proliferation and survival. Human Dead-box protein 3 (DDX3X), a RNA helicase regulating RNA splicing, export, transcription and translation was down-regulated upon MAT1A expression. Our data support the regulation of DDX3X levels by SAM in a concentration and time dependent manner. Consistently, DDX3X arises as a primary target of SAM and a principal intermediate of its antitumoral effect. Based on the parallelism between SAM and DDX3X along the progression of liver disorders, and the results reported here, it is tempting to suggest that reduced SAM in the liver may lead to DDX3X up-regulation contributing to the pathogenic process and that replenishment of SAM might prove to have beneficial effects, at least in part by reducing DDX3X levels. This article is part of a Special Issue entitled: Proteomics: The clinical link.
authors.affiliation: Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Schröder
authors.forename: Joaquín
authors.initials: J
authors.lastname: Fernández-Irigoyen
authors.forename: Emilie
authors.initials: E
authors.lastname: Bigaud
authors.forename: Antonio
authors.initials: A
authors.lastname: Serna
authors.forename: Rubén
authors.initials: R
authors.lastname: Renández-Alcoceba
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000235:genetics*; D046228:Microarray Analysis; D008954:Models, Biological; D020543:Proteome / Q000032:analysis* / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D014162:Transfection
chemical_list: D020543:Proteome; D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases