VPRBP functions downstream of the androgen receptor and OGT to restrict p53 activation in prostate cancer

Abstract

Androgen receptor (AR) is a major driver of prostate cancer (PCa) initiation and progression. O-GlcNAc transferase (OGT), the enzyme that catalyses the covalent addition of UDP-N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of proteins, is often up-regulated in PCa with its expression correlated with high Gleason score. In this study we have identified an AR and OGT co-regulated factor, VPRBP/DCAF1. We show that VPRBP is regulated by the AR at the transcript level, and by OGT at the protein level. In human tissue samples, VPRBP protein expression correlated with AR amplification, OGT overexpression and poor prognosis. VPRBP knockdown in prostate cancer cells led to a significant decrease in cell proliferation, p53 stabilization, nucleolar fragmentation and increased p53 recruitment to the chromatin. In conclusion, we have shown that VPRBP/DCAF1 promotes prostate cancer cell proliferation by restraining p53 activation under the influence of the AR and OGT.