SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer

Guoqiang Li; Weimin Ci; Subhradip Karmakar; Ke Chen; Ruby Dhar; Zhixiang Fan; Zhongqiang Guo; Jing Zhang; Yuwen Ke; Lu Wang; Min Zhuang; Shengdi Hu; Xuesong Li; Liqun Zhou; Xianghong Li; Matthew F Calabrese; Edmond R Watson; Sandip M Prasad; Carrie Rinker-Schaeffer; Scott E Eggener; Thomas Stricker; Yong Tian; Brenda A Schulman; Jiang Liu; Kevin P White

doi:10.1016/j.ccr.2014.02.007

SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer

Cancer Cell. 2014 Apr 14;25(4):455-68. doi: 10.1016/j.ccr.2014.02.007. Epub 2014 Mar 20.

Authors

Guoqiang Li¹, Weimin Ci², Subhradip Karmakar³, Ke Chen⁴, Ruby Dhar³, Zhixiang Fan⁵, Zhongqiang Guo⁶, Jing Zhang⁴, Yuwen Ke⁴, Lu Wang¹, Min Zhuang⁷, Shengdi Hu⁸, Xuesong Li⁹, Liqun Zhou⁹, Xianghong Li¹⁰, Matthew F Calabrese¹¹, Edmond R Watson¹¹, Sandip M Prasad¹², Carrie Rinker-Schaeffer¹², Scott E Eggener¹², Thomas Stricker¹³, Yong Tian⁸, Brenda A Schulman¹⁴, Jiang Liu¹⁵, Kevin P White¹⁶

Affiliations

¹ 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.
² Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
³ 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.
⁴ Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
⁵ Kunming Medical University, Kunming, Yunnan 650500, China.
⁶ 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.
⁷ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Laboratory of Animal Research Center, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁹ Department of Urology, First Hospital of Peking University, Beijing 100034, China.
¹⁰ Department of Pathology, Peking University Cancer Hospital, Beijing 100142, China.
¹¹ Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
¹² Section of Urology, Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
¹³ 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.
¹⁴ 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.
¹⁵ Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: liuj@big.ac.cn.
¹⁶ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinoma, Renal Cell / genetics
Carcinoma, Renal Cell / metabolism*
Carcinoma, Renal Cell / pathology*
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Gene Knockdown Techniques
HEK293 Cells
Heterografts
Humans
Kidney Neoplasms / genetics
Kidney Neoplasms / metabolism*
Kidney Neoplasms / pathology*
Mice
Mice, Inbred BALB C
Mice, Nude
Nuclear Proteins / biosynthesis*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Repressor Proteins / biosynthesis*
Repressor Proteins / genetics
Repressor Proteins / metabolism
Signal Transduction
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Ubiquitination

SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer

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