Elevation of androgen receptor promotes prostate cancer metastasis by induction of epithelial-mesenchymal transition and reduction of KAT5.

Abstract

Androgen receptor (AR), an androgen‐activated transcription factor, belongs to the nuclear receptor superfamily. AR plays an important role in the development and progression of prostate cancer (PCa). However, the role of AR in PCa metastasis is not fully understood. To investigate the role of AR in PCa metastasis, we examined AR expression level in primary and metastatic PCa by analyzing gene array data of 378 primary prostate tumors and 120 metastatic prostate tumors from Oncomine, as well as carrying out immunohistochemical (IHC) staining of 56 prostate cancer samples. Expression of mRNA and protein of AR as well as its target gene prostate‐specific antigen (PSA) was much higher in metastatic prostate tumors than in primary prostate tumors. Knockdown of AR with siRNA or treating with anti‐androgen Casodex reduced migration and invasion ability of C4‐2B PCa cells. Knockdown of AR increased protein expression of E‐cadherin and AR coregulator KAT5 but reduced expression of epithelial‐mesenchymal transition (EMT) marker proteins Slug, Snail, MMP‐2, vimentin, and β‐catenin. Knockdown of KAT5 increased migration of C4‐2B cells, whereas overexpression of KAT5 suppressed cell migration. KAT5 knockdown rescues the suppressive effect of AR knockdown on migration of C4‐2B cells. Gene expression level of AR and KAT5 showed a negative correlation. PCa patients with higher AR expression or lower KAT5 expression correlated with shorter recurrence‐free survival. Our study suggested that elevation of AR expression and AR signaling in prostate tumors promotes PCa metastasis by induction of EMT and reduction of KAT5.