Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer.

Jennifer Munkley,Ling Li,Gerald Hysenaj,Emma Scott,Oliver Thompson,Mads Daugaard,Kathleen Cheung,Ingrid Ehrmann,Caroline Dalgliesh,Bridget Knight,Simon Cockell,Malcolm Crundwell,John Mcgrath,Htoo Zarni Oo,Paul Mccullagh,Sebastian Oltean,Subha Krishnan ,Nuno L Barbosa‐Morais ,Hanna Zielińska ,Lorna W Harries ,Teresa Maia ,Karen E Livermore ,David Elliott

doi:10.7554/elife.47678

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 ESRP2. Both ESRP2 and its close paralog ESRP1 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. ESRP2 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 FLNB and CTNND1. Our data reveals a new mechanism of splicing control in prostate cancer with important implications for disease progression.

Highlights

Prostate is the most common male sex-specific cancer (Center et al, 2012)
Since Epithelial Splicing Regulator Protein 2 (ESRP2) expression was repressed by androgen deprivation therapy (ADT) in patient prostate cancer tissue, we investigated whether androgen receptor (AR) inactivation may influence mRNA splice isoforms that correlate with cancer progression
In this study we report a novel molecular mechanism that explains how androgen steroid hormones control splicing patterns in prostate cancer cells, and unifies the functions of the AR both as a transcription factor and being able to control splicing

Summary

Introduction

Prostate is the most common male sex-specific cancer (Center et al, 2012). Prostate cancer progression is controlled by androgen steroid hormones including testosterone and its active. Munkley et al examined a set of genes that turn off in response to testosteroneblocking drugs in people with prostate cancer This revealed that testosterone controls a master splicing regulator called ESRP2, which is normally present in epithelial cells. Androgens and the AR regulate alternative pre-mRNA splicing through still largely unknown mechanisms (Munkley et al, 2018; Rajan et al, 2011) This represents a very important knowledge gap: alternative splicing patterns in cancer cells can generate protein isoforms with different biological functions (Oltean and Bates, 2014), and is a key process in the generation of biological heterogeneity in prostate cancer (Rajan et al, 2009). Our data identify an AR-ESRP2 axis controlling splicing patterns in prostate cancer cells, and further suggest that reduced ESRP2 levels in response to ADT may inadvertently help prime prostate cancer cells to facilitate longer term disease progression

Results

B RT-qPCR

Discussion

Materials and methods

Funding Funder Prostate Cancer UK