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

Lookup NU author(s): Dr Jennifer Munkley, SR Gokul Krishnan, Gerald Hysenaj, Dr Emma Scott, Caroline Dalgliesh, Kat Cheung, Dr Ingrid Ehrmann, Karen Livermore, Dr Simon Cockell, Professor David Elliott

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

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

Journal: eLife

Year: 2019

Volume: 8

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.

URL: https://doi.org/10.7554/eLife.47678

DOI: 10.7554/eLife.47678


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