Androgen induces G3BP2 and SUMO-mediated p53 nuclear export in prostate cancer

Oncogene. 2017 Nov 9;36(45):6272-6281. doi: 10.1038/onc.2017.225. Epub 2017 Jul 10.

Abstract

The androgen receptor (AR) has a central role in prostate cancer progression, particularly treatment-resistance disease including castration-resistant prostate cancer. Loss of the p53 tumor suppressor, a nuclear transcription factor, is also known to contribute to prostate malignancy. Here we report that p53 is translocated to the cytoplasm by androgen-mediated induction of G3BP2, a newly described direct target gene of AR. G3BP2 induces both cell cycle progression and blocks apoptosis. Translocation of p53 is regulated by androgen-dependent sumoylation mediated by the G3BP2-interacting SUMO-E3 ligase, RanBP2. G3BP2 knockdown results in reduced tumor growth and increased nuclear p53 accumulation in mouse xenograft models of prostate cancer with or without long-term androgen deprivation. Moreover, strong cytoplasmic p53 localization is correlated clinically with elevated G3BP2 expression and predicts poor prognosis and disease progression to the hormone-refractory state. Our findings reveal a new AR-mediated mechanism of p53 inhibition that promotes treatment-resistant prostate cancer.

MeSH terms

  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing
  • Androgens / deficiency
  • Androgens / metabolism*
  • Animals
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Disease Progression
  • Heterografts
  • Humans
  • Male
  • Mice
  • Molecular Chaperones / metabolism*
  • Nuclear Pore Complex Proteins / metabolism*
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • RNA-Binding Proteins
  • Receptors, Androgen / metabolism
  • Sumoylation
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • AR protein, human
  • Adaptor Proteins, Signal Transducing
  • Androgens
  • Carrier Proteins
  • G3BP2 protein, human
  • Molecular Chaperones
  • Nuclear Pore Complex Proteins
  • RNA-Binding Proteins
  • Receptors, Androgen
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ran-binding protein 2