Abstract
Splicing dysregulation frequently occurs in cancers, yet the functional implications of most mis-spliced genes remain elusive. Through a comprehensive pan-cancer analysis of splicing dysregulation, we identified universally mis-spliced genes in cancers and were surprised to find their significant functional enrichment in cell migration. Interestingly, the STE20-like protein kinase (SLK) gene encoding a scaffold protein showed a significant splicing shift from SLK-S to SLK-L isoforms across various cancer types. Detailed studies demonstrated this splicing shift promoted cancer metastasis in cellular and animal models. Mechanistically, RNA-binding Fox-1 Homolog 2 (RBFOX2) protein was identified as a splicing factor that regulates SLK splicing. The two isoforms interact with occludin with different affinities, contributing to their unique activities in cancer metastasis. Notably, the antisense oligonucleotides designed to suppress SLK-L splicing effectively inhibited cancer migration and invasion. Collectively, this study shows a new splicing switch with a key role in controlling cancer metastasis, shedding light on new cancer therapy via splicing manipulation.