Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer
- Newcastle University, United Kingdom
- University of Exeter, United Kingdom
- University of British Columbia, Canada
- Universidade de Lisboa, Portugal
- Royal Devon and Exeter NHS Foundation Trust, United Kingdom
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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE129540.
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RNAseq analysis of ESRP regulated splicing events in prostate cancerNCBI Gene Expression Omnibus, GSE129540.
Article and author information
Author details
S R Gokul Krishnan
Teresa Mendes Maia
Nuno L Barbosa-Morais
Funding
Prostate Cancer UK (PG12-34)
- Jennifer Munkley
- Emma Scott
- Karen E Livermore
Biotechnology and Biological Sciences Research Council (BB/P006612/1)
- Ingrid Ehrmann
Terry Fox Research Institute (TFRI-NF-PPG)
- Mads Daugaard
Breast Cancer Now (2014NovPR355)
- Caroline Dalgliesh
Prostate Cancer UK (RIA16-ST2-011)
- Jennifer Munkley
- Emma Scott
- Karen E Livermore
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Juan Valcárcel, Centre de Regulació Genòmica (CRG), Spain
Ethics
Animal experimentation: Animal work was performed with the approval of Bristol University animal research ethics committee, according to recommendations of www.nc3rs.org.uk, and the UK Government Home Office (home office license PPL 30/3105). All experiments and procedures were approved by the UK Home office in accordance with the Animals (Scientific Procedures) Act 1986, and the Guide for the Care and Use of Laboratory Animals was followed.
Human subjects: RNA samples from prostate cancer patients were obtained with ethical approval through the Exeter NIHR Clinical Research Facility tissue bank (Ref: STB20). Written informed consent for the use of surgically obtained tissue was provided by all patients.
Version history
- Received: April 12, 2019
- Accepted: September 2, 2019
- Accepted Manuscript published: September 3, 2019 (version 1)
- Version of Record published: October 11, 2019 (version 2)
Copyright
© 2019, Munkley et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer
eLife 8:e47678.
https://doi.org/10.7554/eLife.47678
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