%0 Journal Article
%T Alternative RNA splicing of the GIT1 gene is associated with neuroendocrine prostate cancer
%A Ahn R. Lee
%A Jessica M. Lovnicki
%A Ning Xie
%A Varune R. Ramnarine
%A Xuesen Dong
%A Yu Gan
%J Archive of "Cancer Science".
%D 2019
%R 10.1111/cas.13869
%X Potent androgen receptor pathway inhibition (ARPI) therapies have 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 problem as approximately 20% of CRPC cases bear this subtype¡ªa 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 the present study, we identify that RNA splicing of the G protein©\coupled receptor kinase©\interacting protein 1 (GIT1) gene is a unique event in t©\NEPC patients. Specifically, upregulation of the GIT1©\A splice variant and downregulation of the GIT1©\C variant expressions are associated with t©\NEPC patient tumors, patient©\derived xenografts, and cell models. RNA©\binding assays show that RNA splicing of GIT1 is directly driven by SRRM4 and is associated with the neuroendocrine phenotype in CRPC cohorts. We show that GIT1©\A and GIT1©\C regulate differential transcriptomes in prostate cancer cells, where GIT1©\A regulates genes associated with morphogenesis, neural function, environmental sensing via cell©\adhesion processes, and epigenetic regulation. Consistent with our transcriptomic analyses, we report opposing functions of GIT1©\A and GIT1©\C in the stability of focal adhesions, whereby GIT1©\A promotes focal adhesion stability. In summary, our study is the first to report that alternative RNA splicing of the GIT1 gene is associated with t©\NEPC and reprograms its function involving FA©\mediated signaling and cell processes, which may contribute to t©\NEPC development
%K alternative RNA splicing
%K castration resistant
%K GIT1
%K neuroendocrine prostate cancer
%K SRRM4
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317919/