# G3BP1 Suppresses SPOP Ubiquitin Ligase to Promote Prostate Tumorigenesis

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $482,534

## Abstract

Prostate cancer (PCa) accounts for an estimated 26,120 deaths in 2016 representing the second-greatest
cause of cancer death among men. Recent molecular characterization of PCa has revealed striking genomic
heterogeneity and defined distinct molecular subclasses that may provide insight to the variable clinical course.
Recurrent mutations in SPOP are the most common point mutations in prostate cancer, occurring in about
10% of patients across early and advanced disease. SPOP is a substrate receptor of the Cullin 3-based
ubiquitin ligase, which recruits androgen receptor (AR), TRIM24 and SRC-3 and other key regulators for
ubiquitination and degradation, thereby governing the threshold of AR transcription, DNA damage repair, and
tumor suppression. SPOPmut defines a distinct molecular class of prostate cancer characterized by activation of
AR signaling and impairment of DNA double strand break (DSB) repair with transcriptional response (gene set
signature) similar to that of BRCA1 inactivation. We have interrogated the TCGA RNA-seq datasets on primary
(untreated) prostate cancer to define a SPOPmut transcriptional signature of 213 differentially expressed genes,
and validated in independent RNA-seq cohorts for significant enrichment of this gene set in multiple cohorts of
SPOPmut cases. Surprisingly, we also detected primary prostate tumors without mutation of the SPOP gene,
yet showing the same gene expression characteristics to the SPOP mutant subclass, indicating that other
events can phenocopy SPOP mutations in these primary “SPOPmut-like” PCa.
 To further understand the function and regulation of SPOP in prostate tumorigenesis, we performed
tandem affinity purification coupled with mass spectrometry analysis, and identified G3BP1 as a novel SPOP-
binding protein. G3BP1 is not a substrate of SPOP, but acts as a potent inhibitor of the SPOP ubiquitin ligase.
This first-in-kind SPOP inhibitor revealed previously unrecognized means of SPOP inactivation that is
independent of PCa-associated SPOP gene mutations. Importantly, we detected abnormally high levels of
G3BP1 in PCa either with or without SPOP mutations. We hypothesize that dysregulation of G3BP1 defines a
new subclass of prostate cancer with SPOPmut-like molecular signature, pathophysiological characteristics, and
sensitivity to AR- and PARP targeting therapeutics. This application is built upon the unique and
complementary strengths and resources of a team of investigators in prostate cancer genomics and pathology
(Rubin), molecular classification, clinical management and precision therapy of PCa patients (Barbieri),
computational genomics (Sboner), and cullin-based ubiquitin ligases (Zhou). In this proposal, we will 1)
determine the clinical value of G3BP1 dysregulation in PCa classification and potential therapeutic
implications, 2) determine the biochemical mechanisms underlying SPOP inhibition by G3BP1 and the roles of
this newly discovered G3BP1-SPOP ubiquitin signaling pathway in AR ...

## Key facts

- **NIH application ID:** 10328476
- **Project number:** 5R01CA221152-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Pengbo Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $482,534
- **Award type:** 5
- **Project period:** 2018-01-08 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328476

## Citation

> US National Institutes of Health, RePORTER application 10328476, G3BP1 Suppresses SPOP Ubiquitin Ligase to Promote Prostate Tumorigenesis (5R01CA221152-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328476. Licensed CC0.

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