VPRBP functions downstream of the androgen receptor and OGT to restrict p53 activation in prostate cancer
Poulose N., Forsythe N., Polonski A., Gregg G., Maguire S., Fuchs M., Minner S., Sauter G., McDade SS., Mills IG.
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 highly expressed in PCa with its expression correlated with high Gleason score. In this study we have identified an AR and OGT co-regulated factor, Vpr (HIV-1) binding protein (VPRBP) also known as DDB1 and CUL4 Associated Factor 1 (DCAF1). We show that VPRBP is regulated by the AR at the transcript level, and stabilized by OGT at the protein level. VPRBP knockdown in PCa cells led to a significant decrease in cell proliferation, p53 stabilization, nucleolar fragmentation and increased p53 recruitment to the chromatin. In human prostate tumour samples, VPRBP protein overexpression correlated with AR amplification, OGT overexpression, a shorter time to post-operative biochemical progression and poor clinical outcome. In clinical transcriptomic data, VPRBP expression was positively correlated with the AR and also with AR activity gene signatures. Implications: In conclusion, we have shown that VPRBP/DCAF1 promotes PCa cell proliferation by restraining p53 activation under the influence of the AR and OGT.