title: A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer.
abstract: The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SB-mediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that contribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell line further validate three of these genes, Ncoa2/Src-2, Zfx, and Dtnb, as tumor suppressors in liver cancer. Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis. These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy.
authors.affiliation: Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Kathryn.ODonnell@UTSouthwestern.edu
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: O'Donnell
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Keng
authors.forename: Brian
authors.initials: B
authors.lastname: York
authors.forename: Erin L
authors.initials: EL
authors.lastname: Reineke
authors.forename: Daekwan
authors.initials: D
authors.lastname: Seo
authors.forename: Danhua
authors.initials: D
authors.lastname: Fan
authors.forename: Kevin A T
authors.initials: KA
authors.lastname: Silverstein
authors.forename: Christina T
authors.initials: CT
authors.lastname: Schrum
authors.forename: Wei Rose
authors.initials: WR
authors.lastname: Xie
authors.forename: Loris
authors.initials: L
authors.lastname: Mularoni
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Wheelan
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.forename: Jef D
authors.initials: JD
authors.lastname: Boeke
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods*; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D016147:Genes, Tumor Suppressor; D016259:Genes, myc / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics*; D014183:Transplantation, Heterologous; D019895:Transposases / Q000235:genetics*
chemical_list: D000477:Alkylating Agents; C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D004052:Diethylnitrosamine; D019895:Transposases; C494471:sleeping beauty transposase, human