Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; VIB Center for Medical Biotechnology, VIB, Ghent, Belgium; VIB Proteomics Core, VIB, Ghent, Belgium; Department for Biomolecular Medicine, Ghent University, Ghent, Belgium
Kathleen Cheung
Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
Ingrid Ehrmann
Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom
Karen E Livermore
Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom
Hanna Zielinska
Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom
Oliver Thompson
Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom
Bridget Knight
NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
Paul McCullagh
Department of Pathology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
John McGrath
Exeter Surgical Health Services Research Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
Malcolm Crundwell
Department of Urology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
Lorna W Harries
Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom
Mads Daugaard
Department of Urologic Sciences, University of British Columbia, Vancouver, Canada; Vancouver Prostate Centre, Vancouver, Canada
Simon Cockell
Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
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.
