GSE139074
AKAP8 inhibits tumor metastasis by antagonizing EMT-associated RNA alternative splicing
Tumor metastasis is the most lethal attribute of breast cancer, and the epithelial-mesenchymal transition (EMT) plays an important role in this process. Alternative splicing has been shown to causally contribute to EMT; however, the scope of critical splicing events and the regulatory network of splicing factors that govern them remain largely unexplored. Here we report the identification of A-Kinase Anchor Protein (AKAP8) as an EMT splicing regulatory factor that impedes EMT and breast cancer metastasis. AKAP8 not only is capable of inhibiting splicing activity of the EMT-promoting splicing regulator hnRNPM through protein-protein interaction, it also binds to RNA directly and alters splicing outcomes. Genome-wide analysis revealed that AKAP8-mediated splicing events, specifically in epithelial cells, are reversely regulated during EMT, suggesting that AKAP8 maintains an epithelial cell-state splicing program. Experimental manipulation of a newly identified AKAP8 splicing target calsyntenin-1 (CLSTN1) revealed that splice isoform switching of CLSTN1 is crucial for EMT. Mining breast cancer patient data supports the experimental findings and AKAP8 expression and the alternative splicing of CLSTN1 predict patient survival. Our work demonstrates the essentiality of RNA metabolism that impinges on metastatic breast cancer.  Overall design: PolyA-RNA-sequencing of control and AKAP8  knockdown cell lines. Single end enhanced crosslinking and immunoprecipitation sequencing libraries for AKAP8 and input samples