SRRM4 Drives Neuroendocrine Transdifferentiation of Prostate Adenocarcinoma Under Androgen Receptor Pathway Inhibition.

Abstract

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 repetitive matrix 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.

• Authors: Yinan Li, Nilgun Donmez, Cenk Sahinalp, Ning Xie, Yuwei Wang, Hui Xue, Fan Mo, Himisha Beltran, Martin Gleave, Yuzhuo Wang, Colin Collins, Xuesen Dong
• Journal: European urology (Eur Urol) Vol. 71 Issue 1 Pg. 68-78 (01 2017) ISSN: 1873-7560 [Electronic] Switzerland
• PMID: 27180064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Chemical References

• Nerve Tissue Proteins
• Receptors, Androgen
• SRRM4 protein, human

Topics

• Adenocarcinoma (genetics)
• Alternative Splicing
• Cell Line, Tumor
• Cell Transdifferentiation (genetics)
• Disease Progression
• Humans
• Male
• Nerve Tissue Proteins (genetics)
• Neuroendocrine Cells (physiology)
• Neuroendocrine Tumors (genetics)
• Prostatic Neoplasms, Castration-Resistant (genetics)
• Receptors, Androgen (genetics)
• Sequence Analysis, RNA
• Signal Transduction (genetics)
• Exome Sequencing