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Published on: June 13, 2019
G3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer
Chandrani Mukhopadhyay1, Chenyi Yang1, Limei Xu1
1Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, 10065, USA.
Abstract:
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 Cul3SPOP, suggesting a distinctive mode of Cul3SPOP 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 Cul3SPOP, 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 G3BP1high PCa are more susceptible to AR-targeted therapy.
Insights
A novel G3BP1-SPOP signaling axis promotes prostate cancer (PCa) by inhibiting the tumor suppressor SPOP. This finding identifies a new PCa subtype and suggests susceptibility to AR-targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The SPOP protein acts as a crucial tumor suppressor in the prostate.
- Mechanisms regulating SPOP function, particularly in prostate cancer (PCa), remain poorly understood.
Purpose of the Study:
- To elucidate the regulatory mechanisms of SPOP.
- To identify novel interactors and pathways involved in SPOP inactivation in PCa.
Main Methods:
- Protein-protein interaction studies to identify SPOP interactors.
- Transcriptomic analysis to understand gene expression changes.
- Functional studies to assess the impact of G3BP1 on SPOP activity and PCa progression.
- Androgen Receptor (AR) signaling pathway analysis.
Main Results:
- G3BP1 was identified as a SPOP interactor that competitively inhibits Cul3SPOP E3 ligase activity.
- A G3BP1-SPOP ubiquitin signaling axis was revealed, promoting PCa progression via AR signaling activation.
- AR directly upregulates G3BP1 transcription, creating a feed-forward loop amplifying G3BP1-SPOP signaling.
- A PCa cohort with high G3BP1 expression, independent of SPOP mutation, was defined.
Conclusions:
- G3BP1 plays a key role in inactivating the tumor suppressive Cul3SPOP complex.
- This study defines a significant subset of PCa characterized by defective SPOP ubiquitin ligase activity due to G3BP1.
- G3BP1high PCa exhibits increased susceptibility to androgen receptor-targeted therapies.
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