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

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. "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.

http://linkinghub.elsevier.com/retrieve/pii/S2211124714000308

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