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Although endometrial cancer is the most common cancer of the female reproductive tract, we have little understanding of what controls endometrial cancer beyond the transcriptional effects of steroid hormones such as estrogen. As a result, we have limited therapeutic options for the ~62,000 women diagnosed with endometrial cancer each year in the United States. Here, in an attempt to identify new prognostic and therapeutic targets, we focused on a new area for this cancer—alternative mRNA splicing—and investigated whether splicing factor, SF3B1, plays an important role in endometrial cancer pathogenesis. Using a tissue microarray, we found that human endometrial tumors expressed more SF3B1 protein than non-cancerous tissues. Furthermore,  SF3B1  knockdown reduced in vitro proliferation, migration, and invasion of the endometrial cancer cell lines Ishikawa and AN3CA. Similarly, the SF3B1 inhibitor, Pladienolide-B (PLAD-B), reduced the Ishikawa and AN3CA cell proliferation and invasion in vitro. Moreover, PLAD-B reduced tumor growth in an orthotopic endometrial cancer mouse model. Using RNA-Seq approach, we identified ~2000 differentially expressed genes (DEGs) with  SF3B1  knockdown in endometrial cancer cells. Additionally, alternative splicing (AS) events analysis revealed that  SF3B1  depletion led to alteration in multiple categories of AS events including alternative exon skipping (ES), transcript start site usage (TSS), and transcript termination site (TTS) usage. Subsequently, bioinformatics analysis showed  KSR2  as a potential candidate for  SF3B1- mediated functions in endometrial cancer. Specifically, loss of  SF3B1  led to decrease in KSR2 expression, owing to reduced maturation of  KSR2  pre-mRNA to a mature RNA. Importantly, we found rescuing the  KSR2  expression with  SF3B1  knockdown partially restored the cell growth of endometrial cancer cells. Taken together, our data suggest that  SF3B1  plays a crucial oncogenic role in the tumorigenesis of endometrial cancer and hence may support the development of SF3B1 inhibitors to treat this disease.

Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation