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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Munkley J, Li L, Krishnan SRG, Hysenaj G, Scott E, Dalgliesh C, Oo HZ, Maia TM, Cheung K, Ehrmann I, Livermore KE, Zielinska H, Thompson O, Knight B, McCullagh P, McGrath J, Crundwell M, Harries LW, Daugaard M, Cockell S, Barbosa-Morais NL, Oltean S, Elliott DJ
Publication type: Article
Publication status: Published
Online publication date: 03/09/2019
Acceptance date: 02/09/2019
Date deposited: 13/10/2019
ISSN (electronic): 2050-084X
Publisher: eLife Sciences Publications Ltd.
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