GSE129540
RNAseq analysis of ESRP regulated splicing events in prostate cancer
Progression of prostate cancer -the most frequent cancer in men- is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription in prostate cancer cells by stimulating androgen receptor (AR) activity, but also control pre-mRNA splicing through less clear mechanisms. Here we examine whether androgens regulate splicing through AR-mediated transcriptional control of splicing regulator proteins. Supporting this mechanism we find AR controls ESRP2, which encodes a key epithelial-specific splicing regulator. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer, and slow growth of prostate cancer xenografts in mice. 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 after treatment. 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 Casodex®. Our data reveal a new mechanism of splicing control in prostate cancer with important implications for disease progression. Overall design: LNCaP cells (passage 19) were treated with either control siRNAs or siRNAs targeting ESRP1 and ESRP2 for 72 hours (samples prepared in triplicate)