Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer
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 me...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/47678 |
| _version_ | 1811201313966391296 |
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| author | Jennifer Munkley Ling Li S R Gokul Krishnan Gerald Hysenaj Emma Scott Caroline Dalgliesh Htoo Zarni Oo Teresa Mendes Maia Kathleen Cheung Ingrid Ehrmann Karen E Livermore Hanna Zielinska Oliver Thompson Bridget Knight Paul McCullagh John McGrath Malcolm Crundwell Lorna W Harries Mads Daugaard Simon Cockell Nuno L Barbosa-Morais Sebastian Oltean David J Elliott |
| author_facet | Jennifer Munkley Ling Li S R Gokul Krishnan Gerald Hysenaj Emma Scott Caroline Dalgliesh Htoo Zarni Oo Teresa Mendes Maia Kathleen Cheung Ingrid Ehrmann Karen E Livermore Hanna Zielinska Oliver Thompson Bridget Knight Paul McCullagh John McGrath Malcolm Crundwell Lorna W Harries Mads Daugaard Simon Cockell Nuno L Barbosa-Morais Sebastian Oltean David J Elliott |
| author_sort | Jennifer Munkley |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:18:50Z |
| format | Article |
| id | doaj.art-4a90da626b1545618d58b1a38a177512 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:18:50Z |
| publishDate | 2019-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4a90da626b1545618d58b1a38a1775122022-12-22T03:52:10ZengeLife Sciences Publications LtdeLife2050-084X2019-09-01810.7554/eLife.47678Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancerJennifer Munkley0https://orcid.org/0000-0002-8631-4531Ling Li1S R Gokul Krishnan2https://orcid.org/0000-0003-4886-2710Gerald Hysenaj3Emma Scott4Caroline Dalgliesh5Htoo Zarni Oo6Teresa Mendes Maia7https://orcid.org/0000-0003-0038-9629Kathleen Cheung8Ingrid Ehrmann9Karen E Livermore10Hanna Zielinska11Oliver Thompson12Bridget Knight13Paul McCullagh14John McGrath15Malcolm Crundwell16Lorna W Harries17Mads Daugaard18Simon Cockell19Nuno L Barbosa-Morais20https://orcid.org/0000-0002-1215-0538Sebastian Oltean21David J Elliott22https://orcid.org/0000-0002-6930-0699Institute of Genetic Medicine, University of Newcastle, Newcastle, United KingdomInstitute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United KingdomInstitute of Genetic Medicine, University of Newcastle, Newcastle, United KingdomInstitute of Genetic Medicine, University of Newcastle, Newcastle, United KingdomInstitute of Genetic Medicine, University of Newcastle, Newcastle, United KingdomInstitute of Genetic Medicine, University of Newcastle, Newcastle, United KingdomDepartment of Urologic Sciences, University of British Columbia, Vancouver, Canada; Vancouver Prostate Centre, Vancouver, CanadaInstituto 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, BelgiumBioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, United KingdomInstitute of Genetic Medicine, University of Newcastle, Newcastle, United KingdomInstitute of Genetic Medicine, University of Newcastle, Newcastle, United KingdomInstitute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United KingdomInstitute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United KingdomNIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, United KingdomDepartment of Pathology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United KingdomExeter Surgical Health Services Research Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, United KingdomDepartment of Urology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United KingdomInstitute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United KingdomDepartment of Urologic Sciences, University of British Columbia, Vancouver, Canada; Vancouver Prostate Centre, Vancouver, CanadaBioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, United KingdomInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, PortugalInstitute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter, United KingdomInstitute of Genetic Medicine, University of Newcastle, Newcastle, United KingdomProstate 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.https://elifesciences.org/articles/47678RNAsplicinggene expressioncancer |
| spellingShingle | Jennifer Munkley Ling Li S R Gokul Krishnan Gerald Hysenaj Emma Scott Caroline Dalgliesh Htoo Zarni Oo Teresa Mendes Maia Kathleen Cheung Ingrid Ehrmann Karen E Livermore Hanna Zielinska Oliver Thompson Bridget Knight Paul McCullagh John McGrath Malcolm Crundwell Lorna W Harries Mads Daugaard Simon Cockell Nuno L Barbosa-Morais Sebastian Oltean David J Elliott Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer eLife RNA splicing gene expression cancer |
| title | Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer |
| title_full | Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer |
| title_fullStr | Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer |
| title_full_unstemmed | Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer |
| title_short | Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer |
| title_sort | androgen regulated transcription of esrp2 drives alternative splicing patterns in prostate cancer |
| topic | RNA splicing gene expression cancer |
| url | https://elifesciences.org/articles/47678 |
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