title: SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer.
abstract: Hypoxic stress and hypoxia-inducible factors (HIFs) play important roles in a wide range of tumors. We demonstrate that SPOP, which encodes an E3 ubiquitin ligase component, is a direct transcriptional target of HIFs in clear cell renal cell carcinoma (ccRCC). Furthermore, hypoxia results in cytoplasmic accumulation of SPOP, which is sufficient to induce tumorigenesis. This tumorigenic activity occurs through the ubiquitination and degradation of multiple regulators of cellular proliferation and apoptosis, including the tumor suppressor PTEN, ERK phosphatases, the proapoptotic molecule Daxx, and the Hedgehog pathway transcription factor Gli2. Knockdown of SPOP specifically kills ccRCC cells, indicating that it may be a promising therapeutic target. Collectively, our results indicate that SPOP serves as a regulatory hub to promote ccRCC tumorigenesis.
authors.affiliation: Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Li
authors.affiliation: Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Ci
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago and Argonne National Laboratory, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Subhradip
authors.initials: S
authors.lastname: Karmakar
authors.affiliation: Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago and Argonne National Laboratory, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ruby
authors.initials: R
authors.lastname: Dhar
authors.affiliation: Kunming Medical University, Kunming, Yunnan 650500, China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; Department of Urology, First Hospital of Peking University, Beijing 100034, China.
authors.forename: Zhongqiang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhuang
authors.affiliation: Laboratory of Animal Research Center, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shengdi
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Urology, First Hospital of Peking University, Beijing 100034, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Urology, First Hospital of Peking University, Beijing 100034, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Peking University Cancer Hospital, Beijing 100142, China.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Calabrese
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Edmond R
authors.initials: ER
authors.lastname: Watson
authors.affiliation: Section of Urology, Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sandip M
authors.initials: SM
authors.lastname: Prasad
authors.affiliation: Section of Urology, Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Rinker-Schaeffer
authors.affiliation: Section of Urology, Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Eggener
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago and Argonne National Laboratory, Chicago, IL 60637, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stricker
authors.affiliation: Laboratory of Animal Research Center, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Schulman
authors.affiliation: Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: liuj@big.ac.cn.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago and Argonne National Laboratory, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA; Section on Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: kpwhite@uchicago.edu.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: White
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D009687:Nuclear Proteins; D012097:Repressor Proteins; C509761:SPOP protein, human; D044767:Ubiquitin-Protein Ligases