title: Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants.
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.
authors: 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.
authors: Jian
authors: J
authors: An
authors: State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, China.
authors: Chenji
authors: C
authors: Wang
authors: Laboratory of Cancer Genetics, The University of Minnesota Hormel Institute, Austin, MN 55912, USA.
authors: Yibin
authors: Y
authors: Deng
authors: 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.
authors: Long
authors: L
authors: Yu
authors: 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.
authors: Haojie
authors: H
authors: Huang
mesh_terms: D000595:Amino Acid Sequence; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D001665:Binding Sites; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D054875:Ubiquitination
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011944:Receptors, Androgen; D012097:Repressor Proteins; C509761:SPOP protein, human