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

Abstract

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.

Systematic Analysis of Survival-Associated Alternative Splicing Signatures in Thyroid Carcinoma

“…High-throughput sequencing technology can be used to identify various biomarkers at the gene level, such as new alternative splicing events, which are closely related to the survival of patients (13). In recent decades, a large number of studies have confirmed that AS disorders promote the occurrence and development of cancer by dysregulating cell proliferation, invasion, metastasis, apoptosis, drug dependence, and immune escape (14)(15)(16). For instance, tyrosine kinase inhibitors (TKIs) are used to treat leukemia with a BCR-ABL fusion gene, and abnormally spliced mRNA precursors after BCR-ABL transcription are often found that lack the target domain of TKIs and allow tumor cells to escape killing by drugs (17,18).…”

Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination

“…Consistent with previous transcriptomic analyses, opposing functions of GIT1-A and GIT1-C in the stability of focal adhesions was reported, whereby GIT1-A promotes focal adhesion stability. In summary, this previous 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 [ 143 ].…”

Application of magnetic nanoparticles in nucleic acid detection

“…Through gene sequencing, it can be seen that lung cancer-related genes such as epidermal growth factor receptor gene mutation, c-MET, ROS1, KRAS, and BRAF, play an extremely important role in diagnosis and treatment of lung cancer [57][58][59][60][61][62][63][64][65][66][67][68][69][70][71]. In addition to the above diseases, many diseases are related to gene mutations, such as Type 1 diabetes mellitus [72][73][74][75] and Type 2 diabetes mellitus [76][77][78][79][80][81], Lymphoma [82,83], bowel cancer [84][85][86][87][88], and prostatic cancer [89][90][91]. Early nucleic acid detection is significant for identifying these gene mutations to prevent, treat, and identify disease prognosis [92].…”