期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27024-x
关键词
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资金
- US Department of Defense [W81XWH-17-1-0176]
- Prostate Cancer Foundation Challenging Grant [R01 CA125612]
- Krebsliga Cancer Research Grant
- [P50 CA211024]
- [R01 CA221152]
- [R01 CA213992]
- [R37 CA215040]
- [R01 233650]
This study reveals that G3BP1 acts as a competitive inhibitor of SPOP, promoting tumorigenesis in prostate cancer by activating androgen signaling. Furthermore, AR directly upregulates G3BP1 transcription to amplify G3BP1-SPOP signaling in a feed-forward manner.
SPOP functions as a tumour suppressor in prostate cancer but how the protein is regulated is unclear. Here, the authors identify G3BP1 as a competitive inhibitor of SPOP and show that G3BP1-SPOP axis activates androgen signalling to drive tumorigenesis. SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3(SPOP), suggesting a distinctive mode of Cul3(SPOP) inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3(SPOP), thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1(high) PCa are more susceptible to AR-targeted therapy.
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