Destruction of Full-Length Androgen Receptor by Wild-Type SPOP, but Not Prostate-Cancer-Associated Mutants

• Published in: Cell reports (Cambridge) 2014-02, Vol.6 (4), p.657-669
• Main Authors: An, Jian, Wang, Chenji, Deng, Yibin, Yu, Long, Huang, Haojie
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Androgen Receptor Antagonists - pharmacology; Androgens - pharmacology; Binding Sites; Cell Growth Processes; Cell Line, Tumor; HEK293 Cells; Humans; Male; Molecular Sequence Data; Mutation; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteolysis; Receptors, Androgen - metabolism; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; Transcription, Genetic; Ubiquitination
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.01.013

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. [Display omitted] •AR is a bona fide ubiquitination degradation substrate of SPOP E3 ligase•AR splicing variants are resistant to SPOP-mediated degradation•Prostate-cancer-associated SPOP mutants cannot bind to and promote AR degradation•Androgens antagonize but antiandrogens promote SPOP-mediated degradation of AR The SPOP E3 ubiquitin ligase gene is frequently mutated in human prostate cancers. Yu, Huang, and colleagues identify androgen receptor, a major prostate cancer promoter, as a bona fide ubiquitination degradation substrate of SPOP. This effect of SPOP is abolished by prostate-cancer-associated mutations in SPOP and androgen receptor splice variants. This study reveals a tumor-suppressor role of SPOP, suggesting the importance of SPOP mutation and androgen receptor alternative splicing in development of antiandrogen therapy resistance in prostate cancer.