Inhibition of castration‐resistant prostate cancer by the cancer/testis antigen PAGE4, a novel corepressor of the androgen receptor

Abstract

Cellular homeostasis and function of the prostate is regulated by androgens and mediated via the androgen receptor (AR), whose activity is regulated by coactivator and corepressor proteins that enhance or silence AR, respectively. Aberrant reactivation of AR signaling is a pivotal mechanism by which tumors escape androgen‐ablation therapy, the current mainstay systemic treatment for prostate cancer (PCa), which is the second leading cause of cancer death in the US. Prostate‐associated gene 4 (PAGE4) is a member of GAGE‐related cancer/testis antigens, with expression in males confined to prostate and testis. PAGE4 overexpression in LNCaP cells (an AR+ PCa cell line) attenuates AR activity in luciferase assays, reduces androgenic proliferative response and expression of the androgen‐regulated gene Prostate Specific Antigen (PSA). Consistently siRNA‐mediated PAGE4 knockdown potentiates nuclear receptor activity and increases endogenous gene expression. Collectively these data indicate that PAGE4 is a novel AR corepressor. Using LNCaP xenografts to study tumor progression following castration‐mediated androgen depletion, loss of PAGE4 was observed, which temporally correlated with tumor regrowth, AR reactivation and resumed PSA expression. Moreover, tumor incidence and growth was significantly impaired in xenografts overexpressing PAGE4 under androgen‐depleted conditions. Thus by inhibiting AR activity PAGE4 prevents AR reactivation following androgen depletion and thereby prevents tumor progression. Targeting PAGE4 may thus represent a novel therapeutic strategy for advanced PCa.