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

Ahn R Lee, Yu Gan, Ning Xie, Varune R Ramnarine, Jessica M Lovnicki, Xuesen Dong
Cancer Science 2018 November 12
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-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 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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Trending Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"