G3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer

Chandrani Mukhopadhyay, Chenyi Yang, Limei Xu, Deli Liu, Yu Wang, Dennis Huang, Lesa Dayal Deonarine, Joanna Cyrta, Elai Davicioni, Andrea Sboner, Brian. D. Robinson, Arul M. Chinnaiyan, Mark A. Rubin, Christopher E. Barbieri and Pengbo Zhou ()
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Chandrani Mukhopadhyay: Weill Medical College of Cornell University
Chenyi Yang: Weill Medical College of Cornell University
Limei Xu: Weill Medical College of Cornell University
Deli Liu: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Yu Wang: Weill Medical College of Cornell University
Dennis Huang: Weill Cornell Medicine
Lesa Dayal Deonarine: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Joanna Cyrta: Weill Medical College of Cornell University
Elai Davicioni: GenomeDx Bioscience
Andrea Sboner: Weill Medical College of Cornell University
Brian. D. Robinson: Weill Medical College of Cornell University
Arul M. Chinnaiyan: Michigan Center for Translational Pathology, University of Michigan
Mark A. Rubin: Weill Medical College of Cornell University
Christopher E. Barbieri: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Pengbo Zhou: Weill Medical College of Cornell University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27024-x

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