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 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.

Glucose deprivation triggers DCAF1-mediated inactivation of Rheb-mTORC1 and promotes cancer cell survival

“…2A–D ), and Rheb primarily expressed in the cytoplasm (Supplementary Fig. S2E ), which was consistent with observations of previous studies [ 21 , 22 , 38 ]. Co-localization analysis revealed that DCAF1 and Rheb co-localized in the cytoplasm (Fig.…”

Integrating single-cell RNA-sequencing and bulk RNA-sequencing data to explore the role of mitophagy-related genes in prostate cancer

“…Zhang et al also identified ADH5 as a prognosis-related gene by bioinformatics analysis [ 20 ]. Studies by Ninu Poulose et al have shown that VPRBP/DCAF1 promotes prostate cancer cell proliferation by inhibiting p53 activation under the influence of AR and OGT [ 21 ]. Furthermore, MYO6 is strongly associated with Gleason score in prostate cancer [ 22 ].…”

DCAF1 promotes gastric cancer progression by PI3K/AKT/mTOR pathway

“…DCAF1 and CRL4-DDB1-Rbx1 jointly form E3 ubiquitin ligase 17 , which is involved in the regulation of life activities such as cell growth, development, differentiation and apoptosis 16,18,19 . Previous studies have found that DCAF1 is closely related to the occurrence and development of glial cancers, colon cancer and prostatic cancer [20][21][22] . However, the role and prognosis of DCAF1 in GC are still lacking.…”