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

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

Author information

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.

PMID:
24656772
PMCID:
PMC4443692
DOI:
10.1016/j.ccr.2014.02.007
[Indexed for MEDLINE]
Free PMC Article

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