title: Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9.
abstract: The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research.
authors: Bing
authors: B
authors: Yu
authors: Proteomics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Stephen
authors: S
authors: Swatkoski
authors: Genitourological Cancer Branch, Center for Cancer Research, National Cancer Institute, and.
authors: Alesia
authors: A
authors: Holly
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research.
authors: Liam C
authors: LC
authors: Lee
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research.
authors: Valentin
authors: V
authors: Giroux
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research.
authors: Chih-Shia
authors: CS
authors: Lee
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research.
authors: Dennis
authors: D
authors: Hsu
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research.
authors: Jordan L
authors: JL
authors: Smith
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research.
authors: Garmen
authors: G
authors: Yuen
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research.
authors: Junqiu
authors: J
authors: Yue
authors: Department of Molecular Pharmacology, Beckman Research Institute of City of Hope, Duarte, CA 91010; and.
authors: David K
authors: DK
authors: Ann
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research.
authors: R Mark
authors: RM
authors: Simpson
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030.
authors: Chad J
authors: CJ
authors: Creighton
authors: Proteomics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors: William D
authors: WD
authors: Figg
authors: Proteomics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Marjan
authors: M
authors: Gucek
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, ji.luo@nih.gov.
authors: Ji
authors: J
authors: Luo
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D048490:raf Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D034741:RNA, Small Interfering; D044763:Ubiquitin-Conjugating Enzymes; D048490:raf Kinases; D018631:ras Proteins; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: KRAS; SUMO; Ubc9; colorectal cancer; transformation