Proliferating cell nuclear antigen directly interacts with androgen receptor and enhances androgen receptor-mediated signaling

Androgen receptor (AR) and/or its constitutively active splicing variants (AR-Vs), such as AR-V7 and ARv567es, is required for prostate cancer cell growth and survival, and cancer progression. Proliferating cell nuclear antigen (PCNA) is preferentially overexpressed in all cancers and executes its functions through interaction with numerous partner proteins. The aim of the present study was to investigate the potential role of PCNA in the regulation of AR activity. An identical consensus sequence of the PCNA-interacting protein-box (PIP-box) was identified at the N-terminus of human, mouse and rat AR proteins. It was found that PCNA complexes with the full-length AR (AR-FL) and AR-V7, which can be attenuated by the small molecule PIP-box inhibitor, T2AA. PCNA also complexes with ARv567es and recombinant AR protein. The PCNA inhibitors, PCNA-I1S and T2AA, inhibited AR transcriptional activity and the expression of AR target genes in LNCaP-AI and 22Rv1 cells, but not in AR-negative PC-3 cells. The knockdown of PCNA expression reduced dihydrotestosterone-stimulated AR transcriptional activity and abolished the inhibitory effect of PCNA-I1S on AR activity. The PCNA inhibitor, PCNA-I1, exerted additive growth inhibitory effects with androgen deprivation and enzalutamide in cells expressing AR-FL or AR-FL/AR-V7, but not in AR-negative PC-3 cells. Finally, R9-AR-PIP, a small peptide mimicking AR PIP-box, was found to bind to GFP-PCNA at K-d of 2.73 mu M and inhibit the expression of AR target genes, AR transcriptional activity and the growth of AR-expressing cells. On the whole, these data strongly suggest that AR is a PCNA partner protein and interacts with PCNA via the PIP-box and that targeting the PCNA-AR interaction may represent an innovative and selective therapeutic strategy against prostate cancer, particularly castration-resistant prostate cancers overexpressing constitutively active AR-Vs.

Automated summary

This study demonstrates that PCNA interacts with AR and its constitutively active variants, and the inhibition of PCNA-AR interaction can suppress AR transcriptional activity and the expression of AR target genes. Targeting the PCNA-AR interaction may represent an innovative and selective therapeutic strategy against prostate cancer, especially castration-resistant prostate cancers overexpressing constitutively active AR-Vs.