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

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.