G3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer.

TitleG3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsMukhopadhyay C, Yang C, Xu L, Liu D, Wang Y, Huang D, Deonarine LDayal, Cyrta J, Davicioni E, Sboner A, Robinson BD, Chinnaiyan AM, Rubin MA, Barbieri CE, Zhou P
JournalNat Commun
Volume12
Issue1
Pagination6662
Date Published2021 Nov 18
ISSN2041-1723
KeywordsAndrogen Receptor Antagonists, Animals, Carcinogenesis, Cell Line, Tumor, Cell Movement, Cell Survival, Cullin Proteins, DNA Helicases, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mutation, Nuclear Proteins, Poly-ADP-Ribose Binding Proteins, Prostatic Neoplasms, Receptors, Androgen, Repressor Proteins, RNA Helicases, RNA Recognition Motif Proteins, Signal Transduction, Ubiquitin-Protein Ligases
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.

DOI10.1038/s41467-021-27024-x
Alternate JournalNat Commun
PubMed ID34795264
PubMed Central IDPMC8602290
Grant ListR01 CA221152 / CA / NCI NIH HHS / United States
R01 CA213992 / CA / NCI NIH HHS / United States
R37 CA215040 / CA / NCI NIH HHS / United States
R01 CA125612 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
Related Faculty: 
Brian Robinson, M.D.

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