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

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: 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
• Journal: eLife (Elife) Vol. 8 (09 03 2019) ISSN: 2050-084X [Electronic] England
• PMID: 31478829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019, Munkley et al.

Chemical References

• Androgens
• ESRP2 protein, human
• RNA-Binding Proteins
• Receptors, Androgen

Topics

• Alternative Splicing (drug effects)
• Androgens (metabolism)
• Cells, Cultured
• Humans
• Male
• Prostatic Neoplasms (pathology)
• RNA-Binding Proteins (biosynthesis, genetics)
• Receptors, Androgen (metabolism)
• Transcription, Genetic