Journal
EUROPEAN UROLOGY
Volume 71, Issue 1, Pages 68-78Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.eururo.2016.04.028
Keywords
Neuroendocrine prostate cancer; AR inhibition; SRRM4; Alternative RNA splicing
Categories
Funding
- Can adian Institutes of Health Research [MOP-137007]
- Prostate Cancer Canada [RS2013-58]
- Urology Foundation (charitable organization) [889494399]
- BC Cancer Foundation [DRG01518, 1NSRG030]
- Genome Canada Grant [176ISO]
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Background: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of castration- resistant prostate cancer that typically does not respond to androgen receptor pathway inhibition (ARPI), and its diagnosis is increasing. Objective: To understand how NEPC develops and to identify driver genes to inform therapy for NEPC prevention. Design, setting, and participants: Whole-transcriptome sequencing data were extracted from prostate tumors from two independent cohorts: The Beltran cohort contained 27 adenocarcinoma and five NEPC patient samples, and the Vancouver Prostate Centre cohort contained three patient samples and nine patient-derived xenografts. Intervention: A novel bioinformatics tool, comparative alternative splicing detection (COMPAS), was invented to analyze alternative RNA splicing on RNA-sequencing data. Outcome measurements and statistical analysis: COMPAS identified potential driver genes for NEPC development. Biochemical and biological validations were performed in both prostate cell and tumor models. Results and limitation: More than 66% of the splice events were predicted to be regulated by the RNA splicing factor serine/arginine repetitivematrix 4 (SRRM4). In vitro and in vivo evidence confirmed that one SRRM4 target gene was the RE1 silencing transcription factor (REST), a master regulator of neurogenesis. Moreover, SRRM4 strongly stimulated adenocarcinoma cells to express NEPC biomarkers, and this effect was exacerbated by ARPI. ARPI combined with a gain of SRRM4-induced adenocarcinoma cells to assume multicellular spheroid morphology and was essential in establishing progressive NEPC xenografts. These SRRM4 actions were further enhanced by loss of function of TP53. Conclusions: SRRM4 drives NEPC progression. This knowledge may guide the development of novel therapeutics aimed at NEPC. Patient summary: Using next-generation RNA sequencing and our newly developed bioinformatics tool, we identified a neuroendocrine prostate cancer (NEPC)-specific RNA splicing signature that is predominantly controlled by serine/arginine repetitive matrix 4 (SRRM4). We confirmed that SRRM4 drives NEPC progression, and we propose SRRM4 as a potential therapeutic target for NEPC. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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