The splicing switch of SLK controls tumor progression partially via different associations with occludin

Aberrant RNA splicing is significantly associated with tumorigenesis and cancer progression. From a pan-cancer transcriptome analysis, we discovered a critical cancer-associated splicing event at exon 13 of SLK that encodes a fragment of 31 amino acids in its coiled-coil domain. We found that alternative skipping of this exon produces a long and short isoform (SLK-L and SLK-S). The splicing is dramatically shifted towards SLK-L across thirteen common cancer types. The two SLK isoforms have distinct functions in controlling cancer development. SLK-L is essential for cancer development while SLK-S leads to cancer repression. Mechanistically, the splicing factor Rbfox2 was identified to specifically bind intron 12 of SLK and inhibit the inclusion of exon 13. Moreover, different SLK isoforms exhibited distinct affinities in binding to the tight junction protein occludin. SLK-L bounds less occludin compared with SLK-S, which may dysregulate the function of tight junctions and disrupt the structural integrity of cells. Finally, we used antisense oligonucleotides to inhibit the inclusion of SLK exon 13, resulting in significant suppression of cancer growth and migration. Collectively, this study uncovered biological consequences and underlying mechanisms for one of the most mis-spliced genes in cancer, shedding light on new cancer therapy via splicing manipulation. ### Competing Interest Statement The authors have declared no competing interest.