Alternative RNA splicing of the GIT1 gene is associated with neuroendocrine prostate cancer

Abstract

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.

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