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Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer.
Elife 2019; 8E

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.

Authors+Show Affiliations

Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom.Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom.Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom.Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom.Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom.Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom.Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. Vancouver Prostate Centre, Vancouver, Canada.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.Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom.Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom.Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom.Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom.Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom.NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.Department of Pathology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.Exeter Surgical Health Services Research Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.Department of Urology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom.Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. Vancouver Prostate Centre, Vancouver, Canada.Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom.Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom.Institute of Genetic Medicine, University of Newcastle, Newcastle, United Kingdom.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31478829

Citation

Munkley, Jennifer, et al. "Androgen-regulated Transcription of ESRP2 Drives Alternative Splicing Patterns in Prostate Cancer." ELife, vol. 8, 2019.
Munkley J, Li L, Krishnan SRG, et al. Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. Elife. 2019;8.
Munkley, J., Li, L., Krishnan, S. R. G., Hysenaj, G., Scott, E., Dalgliesh, C., ... Elliott, D. J. (2019). Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. ELife, 8, doi:10.7554/eLife.47678.
Munkley J, et al. Androgen-regulated Transcription of ESRP2 Drives Alternative Splicing Patterns in Prostate Cancer. Elife. 2019 09 3;8 PubMed PMID: 31478829.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. AU - Munkley,Jennifer, AU - Li,Ling, AU - Krishnan,S R Gokul, AU - Hysenaj,Gerald, AU - Scott,Emma, AU - Dalgliesh,Caroline, AU - Oo,Htoo Zarni, AU - Maia,Teresa Mendes, AU - Cheung,Kathleen, AU - Ehrmann,Ingrid, AU - Livermore,Karen E, AU - Zielinska,Hanna, AU - Thompson,Oliver, AU - Knight,Bridget, AU - McCullagh,Paul, AU - McGrath,John, AU - Crundwell,Malcolm, AU - Harries,Lorna W, AU - Daugaard,Mads, AU - Cockell,Simon, AU - Barbosa-Morais,Nuno L, AU - Oltean,Sebastian, AU - Elliott,David J, Y1 - 2019/09/03/ PY - 2019/04/12/received PY - 2019/09/02/accepted PY - 2019/9/4/pubmed PY - 2019/9/4/medline PY - 2019/9/4/entrez KW - RNA KW - cancer KW - chromosomes KW - gene expression KW - human KW - splicing JF - eLife JO - Elife VL - 8 N2 - 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. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/31478829/Androgen-regulated_transcription_of_ESRP2_drives_alternative_splicing_patterns_in_prostate_cancer L2 - https://doi.org/10.7554/eLife.47678 DB - PRIME DP - Unbound Medicine ER -