RT Journal Article SR Electronic T1 Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer JF bioRxiv FD Cold Spring Harbor Laboratory SP 629618 DO 10.1101/629618 A1 Jennifer Munkley A1 Li Ling A1 S R Gokul Krishnan A1 Gerald Hysenaj A1 Emma Scott A1 Htoo Zarni Oo A1 Teresa M. Maia A1 Kat Cheung A1 Ingrid Ehrmann A1 Karen E. Livermore A1 Hanna Zielinska A1 Oliver Thompson A1 Bridget Knight A1 Paul McCullagh A1 John McGrath A1 Malcolm Crundwell A1 Lorna W. Harries A1 Mads Daugaard A1 Simon Cockell A1 Nuno L. Barbosa-Morais A1 Sebastian Oltean A1 David J Elliott YR 2019 UL http://biorxiv.org/content/early/2019/05/08/629618.abstract 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.