Regulation of androgen receptor splice variant AR3 by PCGEM1.

Ziqiang Zhang,Chunxue Bai,Fangting Wu,Yin-Yuan Mo,Xinchun Zhou,Jianguo Huang,Tsui-Ting Ho,Nanjiang Zhou,Zhuxian Zhu,Min Xu,Zhongmin Qiu

doi:10.18632/oncotarget.7139

Abstract

The androgen receptor (AR) is required for prostate development and is also a major driver of prostate cancer pathogenesis. Thus androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. However, castration resistance due to expression of constitutively active AR splice variants is a significant challenge to prostate cancer therapy; little is known why effectiveness of ADT can only last for a relatively short time. In the present study, we show that PCGEM1 interacts with splicing factors heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and U2AF65, as determined by RNA precipitation and Western blot, suggesting a role for PCGEM1 in alternative splicing. In support of this possibility, PCGEM1 is correlated with AR3, a predominant and clinically important form of AR splice variants in prostate cancer. Moreover, androgen deprivation (AD) induces PCGEM1 and causes its accumulation in nuclear speckles. Finally, we show that the AD-induced PCGEM1 regulates the competition between hnRNP A1 and U2AF65 for AR pre-mRNA. AD promotes PCGEM1 to interact with both hnRNP A1 and U2AF65 with different consequences. While the interaction of PCGEM1 with hnRNP A1 suppresses AR3 by exon skipping, its interaction with U2AF65 promotes AR3 by exonization. Together, we demonstrate an AD-mediated AR3 expression involving PCGEM1 and splicing factors.

Highlights

Prostate cancer is the most common malignancy among elderly men in Western countries
A recent report showed that PCGEM1 and PRNCR1 interact with androgen receptor (AR), impacting AR regulated gene expression [18]
We performed RNA precipitation experiments using the biotin-labelled PCGEM1 RNA probe to identify PCGEM1 binding partners. This approach combined with PAGE analysis and mass-spectrometry analysis suggested that heterogeneous nuclear ribonucleoprotein A1 was a potential PCGEM1 binding partner (Fig. 1A; Fig. S1)

Summary

Introduction

Prostate cancer is the most common malignancy among elderly men in Western countries. Initial response of prostate cancer to ADT is effective, these patients inevitably develop the resistance, i.e., castrationresistant prostate cancer (CRPC) [1, 2]. This is a major obstacle for improving overall survival in prostate cancer. This ADT-induced castration resistance has been known for a long time, the underlying mechanism is still elusive. AR3 (AR-V7) is one of the major AR splice variants which can play a significant role in castration resistance [5, 6]. It has been shown that circulating AR3 is associated with the resistance to two clinically important drugs enzalutamide and abiraterone [7]

Methods

Results

Conclusion