Potent androgen receptor pathway inhibition (ARPI) therapies has given rise to a lethal, aggressive subtype of castration-resistant prostate cancer (CRPC) called treatment-induced neuroendocrine prostate cancer (t-NEPC). Now, t-NEPC poses a major clinical issue as ~20% of CRPC cases bear this subtype-a rate of occurrence that is predicted to rise with the widespread use of ARPI therapies. Unfortunately, there are no targeted therapies currently available to treat t-NEPC, as the origin and molecular underpinnings of t-NEPC development remain unclear. In this study, we identify that the RNA splicing of the G protein-coupled receptor kinase-interacting protein 1 (GIT1) gene is a unique event in t-NEPC patients. Specifically, the up-regulation of the GIT1-A splice variant and down-regulation of the GIT1-C variant are associated with t-NEPC progression in patient tumors, as well as mouse and cell models, when compared to expression in the prostate adenocarcinoma subtype. RNA-binding assays reveal that the RNA splicing of GIT1 is directly driven by SRRM4 and is associated with its expression in CRPC cohorts. We show that GIT1-A and GIT1-C regulate differential transcriptomes in prostate cancer cells, where GIT1-A is enriched with genes associated with cell morphogenesis and neural functions. In summary, our study is the first to report that alternative RNA splicing of the GIT1 gene is associated with t-NEPC and may regulate transcriptomes implicated in t-NEPC progression. This article is protected by copyright. All rights reserved.
Cancer science. 2018 Nov 12 [Epub ahead of print]
Ahn R Lee, Yu Gan, Ning Xie, Varune R Ramnarine, Jessica M Lovnicki, Xuesen Dong
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, Canada, V6H 3Z6.