Androgen-regulated transcription of <i>ESRP2</i> drives alternative splicing patterns in prostate cancer.

Abstract

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator <i>ESRP2</i>. Both <i>ESRP2</i> and its close paralog <i>ESRP1</i> are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including splicing switches correlating with disease progression. <i>ESRP2</i> expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, treatment with the AR antagonist bicalutamide (Casodex) induced mesenchymal splicing patterns of genes including <i>FLNB</i> and <i>CTNND1</i>. Our data reveals a new mechanism of splicing control in prostate cancer with important implications for disease progression.