Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

  1. Jennifer Munkley
  2. Li Ling
  3. S R Gokul Krishnan
  4. Gerald Hysenaj
  5. Emma Scott
  6. Htoo Zarni Oo
  7. Teresa M. Maia
  8. Kat Cheung
  9. Ingrid Ehrmann
  10. Karen E. Livermore
  11. Hanna Zielinska
  12. Oliver Thompson
  13. Bridget Knight
  14. Paul McCullagh
  15. John McGrath
  16. Malcolm Crundwell
  17. Lorna W. Harries
  18. Mads Daugaard
  19. Simon Cockell
  20. Nuno L. Barbosa-Morais
  21. Sebastian Oltean
  22. David J Elliott
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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 a key splicing switch in the metastatic regulator FLNB which is associated with disease relapse. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, FLNB splicing was reciprocally switched by the AR antagonist bicalutamide (Casodex ® ). Our data reveal a new mechanism of splicing control in prostate cancer with important implications for metastatic disease progression.

Key points

  • Transcriptional regulation of ESRP2 by the androgen receptor controls splice isoform patterns in prostate cancer cells.

  • Splicing switches regulated by the androgen-ESRP2 axis include a splice isoform in the FLNB gene that is a known metastatic driver.

  • Both ESRP1 and ESRP2 are highly expressed in prostate cancer tissue.

  • Ectopic expression of ESRP1 and 2 inhibits prostate cancer cell growth.

  • By repressing ESRP2 expression androgen deprivation therapy (ADT) may dampen epithelial splicing programmes to inadvertently prime disease progression towards metastasis.

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