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 ofwhich lack the hinge domain, escape SPOP-mediated degradation. Prostate-cancer-associated mutants of SPOP cannot bind to and promote ARdestruction. 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 657-669 |
| Number of pages | 13 |
| Journal | Cell reports |
| Volume | 6 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2014 |
Bibliographical note
Funding Information:We would like to thank Dr. Donald Tindall for reagents and critical reading and constructive comments on the manuscript and Dr. Zijie Sun for plasmids. This work was supported in part by grants from the National Institutes of Health (CA134514 and CA130908 to H.H., and CA155522 to Y.D.), the Department of Defense (W81XWH-09-1-622 to H.H.), and National Natural Science Foundation of China (30872947, 31071193, and 81171964 to L.Y.).
