title: A DNA methylation signature associated with the epigenetic repression of glycine N-methyltransferase in human hepatocellular carcinoma.
abstract: The basic mechanisms underlying promoter DNA hypermethylation in cancer are still largely unknown. It has been proposed that the levels of the methyl donor group in DNA methylation reactions, S-adenosylmethionine (SAMe), might be involved. SAMe levels depend on the glycine-N-methyltransferase (GNMT), a one-carbon group methyltransferase, which catalyzes the conversion of SAMe to S-adenosylhomocysteine in hepatic cells. GNMT has been proposed to display tumor suppressor activity and to be frequently repressed in hepatocellular carcinoma (HCC). In this study, we show that GNMT shows aberrant DNA hypermethylation in some HCC cell lines and primary tumors (20 %). GNMT hypermethylation could contribute to gene repression and its restoration in cell lines displaying hypermethylation-reduced tumor growth in vitro. In agreement, human primary tumors expressing GNMT were of smaller size than tumors showing GNMT hypermethylation. Genome-wide analyses of gene promoter methylation identified 277 genes whose aberrant methylation in HCC was associated with GNMT methylation/expression. The findings in this manuscript indicate that DNA hypermethylation plays an important role in the repression of GNMT in HCC and that loss of GNMT in human HCC could promote the establishment of aberrant DNA methylation patterns at specific gene promoters.
authors.affiliation: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Covadonga
authors.initials: C
authors.lastname: Huidobro
authors.forename: Estela G
authors.initials: EG
authors.lastname: Toraño
authors.forename: Agustín F
authors.initials: AF
authors.lastname: Fernández
authors.forename: Rocío G
authors.initials: RG
authors.lastname: Urdinguio
authors.forename: Ramón M
authors.initials: RM
authors.lastname: Rodríguez
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ferrero
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez-Camblor
authors.forename: Loreto
authors.initials: L
authors.lastname: Boix
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.forename: Juan Luís
authors.initials: JL
authors.lastname: García-Rodríguez
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.forename: José María
authors.initials: JM
authors.lastname: Mato
authors.forename: María Luz
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019175:DNA Methylation; D063185:Epigenetic Repression; D050938:Glycine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
chemical_list: D006657:Histones; D012333:RNA, Messenger; D012436:S-Adenosylmethionine; C494510:GNMT protein, human; D050938:Glycine N-Methyltransferase