1. Chromosomes and Gene Expression
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Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

  1. Jennifer Munkley  Is a corresponding author
  2. Li Ling
  3. S R Gokul Krishnan
  4. Gerald Hysenaj
  5. Emma Scott
  6. Caroline Dalgliesh
  7. Htoo Zarni Oo
  8. Teresa Mendes Maia
  9. Kathleen Cheung
  10. Ingrid Ehrmann
  11. Karen E Livermore
  12. Hanna Zielinska
  13. Oliver Thompson
  14. Bridget Knight
  15. Paul McCullagh
  16. John McGrath
  17. Malcolm Crundwell
  18. Lorna W Harries
  19. Mads Daugaard
  20. Simon Cockell
  21. Nuno L Barbosa-Morais  Is a corresponding author
  22. Sebastian Oltean  Is a corresponding author
  23. David J Elliott  Is a corresponding author
  1. Newcastle University, United Kingdom
  2. University of Exeter, United Kingdom
  3. University of British Columbia, Canada
  4. Universidade de Lisboa, Portugal
  5. Royal Devon and Exeter NHS Foundation Trust, United Kingdom
Research Article
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Cite this article as: eLife 2019;8:e47678 doi: 10.7554/eLife.47678

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.

Article and author information

Author details

  1. Jennifer Munkley

    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
    For correspondence
    Jennifer.munkley@ncl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8631-4531
  2. Li Ling

    Institute of Biomedical and Clinical Sciences, University of Exeter, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. S R Gokul Krishnan

    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4886-2710
  4. Gerald Hysenaj

    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Emma Scott

    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Caroline Dalgliesh

    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Htoo Zarni Oo

    Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Teresa Mendes Maia

    Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0038-9629
  9. Kathleen Cheung

    Bioinformatics Support Unit, Newcastle University, Newcastle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Ingrid Ehrmann

    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Karen E Livermore

    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Hanna Zielinska

    Institute of Biomedical and Clinical Sciences, University of Exeter, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Oliver Thompson

    Institute of Biomedical and Clinical Sciences, University of Exeter, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Bridget Knight

    NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Paul McCullagh

    Department of Pathology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. John McGrath

    Exeter Surgical Health Services Research Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Malcolm Crundwell

    Department of Urology, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. Lorna W Harries

    Institute of Biomedical and Clinical Sciences, University of Exeter, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Mads Daugaard

    Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  20. Simon Cockell

    Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  21. Nuno L Barbosa-Morais

    Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
    For correspondence
    nmorais@medicina.ulisboa.pt
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1215-0538
  22. Sebastian Oltean

    Institute of Biomedical and Clinical Sciences, University of Exeter, Exeter, United Kingdom
    For correspondence
    s.oltean@exeter.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  23. David J Elliott

    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
    For correspondence
    David.Elliott@ncl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6930-0699

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.

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.

Reviewing Editor

  1. Juan Valcárcel, Centre de Regulació Genòmica (CRG), Spain

Publication history

  1. Received: April 12, 2019
  2. Accepted: September 2, 2019
  3. Accepted Manuscript published: September 3, 2019 (version 1)

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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