Transformer 2ß regulates alternative splicing of cell cycle regulator genes to promote ovarian cancer cell progression

Poor prognosis of late stage ovarian cancer patients is observed with high metastasis rate, but the underlying molecular mechanism is ambiguous. RNA binding proteins (RBPs) play important roles in post-transcriptional regulation in tumor neoplasia and metastasis. In this study, we dedicated to explore the molecular functions of a canonical RBP, TRA2B, in cancer cells. By knocking TRA2B expression in HeLa cells and performing whole transcriptome sequencing experiment (RNA-seq), we found TRA2B-regulated alternative splicing profile was tightly associated with mitotic cell cycle, apoptosis, and several cancer pathways. Meanwhile, hundreds of genes were regulated by TRA2B at expression level, and their functions were enriched in cell proliferation, cell adhesion and angiogenesis, which were also related to cancer progression. We also observed the AS regulation and expression regulation were independent by integrating AS genes and expression changed genes. We then explored and validated the carcinogenic functions of TRA2B by knocking down its expression in ovarian cancer cells. In vivo, higher expression level of TRA2B was associated with poor prognosis in ovarian cancer patients. In conclusion, we demonstrated the important roles of TRA2B in ovarian cancer neoplasia and progression, and identified the underlying molecular mechanisms, making a contribution to molecular targeting treatment of ovarian cancer in the future. Overall design: In this study, using next-generation RNA sequencing (RNA-seq) technology, we systematically investigated the global TRA2B-regulated AS events and the global gene expression change by silencing the expression of Tra2ß in cancer cells. We found TRA2B could extensively regulate gene expression and AS in HeLa cells, which was highly related to its carcinogenic functions. Silencing experiment of TRA2B in ovarian cells validated its functions in cell proliferation, cell invasion and cell apoptosis in ovarian cancer cells. In summary, we extensively confirmed the carcinogenic functions of TRA2B in ovarian cancer cells, which were completed by regulating the expression and alternative splicing of associated genes.