PT  - JOURNAL ARTICLE
AU  - Jennifer Munkley
AU  - Li Ling
AU  - S R Gokul Krishnan
AU  - Gerald Hysenaj
AU  - Emma Scott
AU  - Htoo Zarni Oo
AU  - Teresa M. Maia
AU  - Kat Cheung
AU  - Ingrid Ehrmann
AU  - Karen E. Livermore
AU  - Hanna Zielinska
AU  - Oliver Thompson
AU  - Bridget Knight
AU  - Paul McCullagh
AU  - John McGrath
AU  - Malcolm Crundwell
AU  - Lorna W. Harries
AU  - Mads Daugaard
AU  - Simon Cockell
AU  - Nuno L. Barbosa-Morais
AU  - Sebastian Oltean
AU  - David J Elliott
TI  - Androgen-regulated transcription of <em>ESRP2</em> drives alternative splicing patterns in prostate cancer
AID  - 10.1101/629618
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 629618
4099  - http://biorxiv.org/content/early/2019/05/09/629618.short
4100  - http://biorxiv.org/content/early/2019/05/09/629618.full
AB  - 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 pointsTranscriptional 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.