Alternative RNA splicing of the GIT 1 gene is associated with neuroendocrine prostate cancer

Autor: Varune Rohan Ramnarine, Ning Xie, Jessica M. Lovnicki, Xuesen Dong, Ahn R. Lee, Yu Gan
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Cancer Research
Cell Cycle Proteins
Nerve Tissue Proteins
Biology
Transcriptome
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Cell
Molecular
and Stem Cell Biology
Downregulation and upregulation
alternative RNA splicing
Cell Line
Tumor
SRRM4
medicine
Humans
Protein Isoforms
Genetic Predisposition to Disease
Epigenetics
Gene
Adaptor Proteins
Signal Transducing
Focal Adhesions
neuroendocrine prostate cancer
Gene Expression Profiling
Alternative splicing
Prostatic Neoplasms
Original Articles
General Medicine
medicine.disease
castration resistant
Carcinoma
Neuroendocrine
3. Good health
Gene Expression Regulation
Neoplastic
Androgen receptor
Alternative Splicing
Gene Ontology
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
PC-3 Cells
RNA splicing
Cancer research
Original Article
GIT1
Zdroj: Cancer Science
ISSN: 1349-7006
1347-9032
DOI: 10.1111/cas.13869
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: