title: Gankyrin activates mTORC1 signaling by accelerating TSC2 degradation in colorectal cancer.
abstract: Gankyrin is overexpressed in some malignancies. However its roles in colorectal carcinogenesis and underlying mechanisms remain largely unexplored. Here we report that gankyrin promotes the initiation and development of colorectal carcinogenesis by activating mTORC1 signaling through TSC/Rheb dependent mechanism. We further show that Gankyrin overexpression accelerated TSC2 degradation, while knockdown in a panel of colorectal cancer (CRC) cell lines, cell line derived xenografts and CRC patient derived xenograft (PDX) tumors delayed TSC2 degradation, restored the TSC2 protein level, and inhibited mTORC1 signaling and CRC growth. Our findings reveal a unique mechanism by which gankyrin promotes colorectal carcinogenesis and show that gankyrin is a potential therapeutic target to improve the clinical management of CRC.
authors.affiliation: Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Qin
authors.affiliation: Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Morris
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China. Electronic address: zhangyanjie@shsmu.edu.cn.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D000076222:Mechanistic Target of Rapamycin Complex 1; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009479:Neuropeptides / Q000378:metabolism; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D000077005:Tuberous Sclerosis Complex 2 Protein; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D046912:Multiprotein Complexes; D009479:Neuropeptides; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; D020559:Monomeric GTP-Binding Proteins
keywords: Colorectal cancer; Gankyrin; TSC2; mTOR