Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer
S R Gokul Krishnan,
Htoo Zarni Oo,
Teresa M. Maia,
Karen E. Livermore,
Lorna W Harries,
Nuno L. Barbosa-Morais,
David J Elliott
Posted 08 May 2019
bioRxiv DOI: 10.1101/629618 (published DOI: 10.7554/eLife.47678)
Posted 08 May 2019
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
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