Abstract 4393: Integrative proteomic analysis of prostate cancer reveals distinct regulation of RNA binding proteins during disease progression

Abstract

Abstract To understand the etiology of the disease, and to find novel and more specific drug targets, the driver mutations and expressional changes in prostate cancer have been examined through extensive genomic and transcriptomic characterization. Although significant insight has been gained through these efforts, it is clear that not all molecular alterations influencing the tumor outcome can be captured through these approaches, and that a comprehensive understanding of the molecular events in cancer require thorough investigation of the proteome. To understand the functional consequences of genetic and transcriptional aberrations in prostate cancer, we aimed to reveal the proteomic changes during disease formation and progression. We performed high throughput mass spectrometry on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration resistant prostate cancer (CRPC). We performed an integrative analysis of the proteomic data with gene copy number, DNA methylation, and RNA expression data from the same samples. Furthermore, proteomic events correlating with the androgen receptor (AR) status of the tumors were analysed. We uncovered previously unrecognized molecular and pathway events and several novel AR-associated events in the prostate cancer proteomes to study further. We found significant changes in expression of RNA-binding proteins during disease formation and progression. Examining the relationship of RNA binding proteins at the RNA and protein expression level reveal that while many RNA binding proteins exhibit correlation between the expression levels, some seem regulated at the posttranslational level. Two RNA binding proteins, TDP-43 and FUS, which regulated at the protein, but not at RNA level during prostate cancer progression, show opposite behavior during disease progression and correlation with AR status of the tumors. In cultured prostate cancer cell models, we show that these proteins have specific, but divergent interactions with AR at the RNA and protein levels, and that they contribute differentially to AR activity-mediated responses. Thus, these proteins may significantly contribute to prostate cancer molecular evolution and may pinpoint possible targetable pathways in future prostate cancer therapy. Citation Format: Mauro Scaravilli, Annika Kohvakka, Pekka Ruusuvuori, Ebrahim Afyounian, Matti Nykter, Tapio Visakorpi, Leena Latonen. Integrative proteomic analysis of prostate cancer reveals distinct regulation of RNA binding proteins during disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4393.