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Cell Rep. 2014 Feb 27;6(4):657-69. doi: 10.1016/j.celrep.2014.01.013. Epub 2014 Feb 6.

Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants.

Author information

1
State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, China; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
2
State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, China.
3
Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
4
State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China. Electronic address: longyu@fudan.edu.cn.
5
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: huang.haojie@mayo.edu.

Abstract

The SPOP E3 ubiquitin ligase gene is frequently mutated in human prostate cancers. Here, we demonstrate that SPOP recognizes a Ser/Thr-rich degron in the hinge domain of androgen receptor (AR) and induces degradation of full-length AR and inhibition of AR-mediated gene transcription and prostate cancer cell growth. AR splicing variants, most of which lack the hinge domain, escape SPOP-mediated degradation. Prostate-cancer-associated mutants of SPOP cannot bind to and promote AR destruction. Furthermore, androgens antagonize SPOP-mediated degradation of AR, whereas antiandrogens promote this process. This study identifies AR as a bona fide substrate of SPOP and elucidates a role of SPOP mutations in prostate cancer, thus implying the importance of this pathway in resistance to antiandrogen therapy of prostate cancer.

PMID:
24508459
PMCID:
PMC4361392
DOI:
10.1016/j.celrep.2014.01.013
[Indexed for MEDLINE]
Free PMC Article

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