G3BP1 inhibits Cul3 SPOP to amplify AR signaling and promote prostate cancer

Nat Commun. 2021 Nov 18;12(1):6662. doi: 10.1038/s41467-021-27024-x.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Receptor Antagonists / pharmacology
  • Animals
  • Carcinogenesis
  • Cell Line, Tumor
  • Cell Movement
  • Cell Survival / drug effects
  • Cullin Proteins / antagonists & inhibitors*
  • Cullin Proteins / metabolism
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Mutation
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins / metabolism*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • RNA Helicases / genetics
  • RNA Helicases / metabolism*
  • RNA Recognition Motif Proteins / genetics
  • RNA Recognition Motif Proteins / metabolism*
  • Receptors, Androgen / metabolism*
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects
  • Ubiquitin-Protein Ligases / antagonists & inhibitors
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Androgen Receptor Antagonists
  • CUL3 protein, human
  • Cullin Proteins
  • Nuclear Proteins
  • Poly-ADP-Ribose Binding Proteins
  • RNA Recognition Motif Proteins
  • Receptors, Androgen
  • Repressor Proteins
  • SPOP protein, human
  • Ubiquitin-Protein Ligases
  • DNA Helicases
  • G3BP1 protein, human
  • RNA Helicases