miR‐200/375 control epithelial plasticity‐associated alternative splicing by repressing the RNA‐binding protein Quaking

Members of the miR-200 family are critical gatekeepersof the epithelial state, restraining expression of pro-mesenchymal genes that drive epithelial-mesenchymal transition(EMT) and contribute to metastatic cancer progression. Here, we show that miR-200c and another epithelial-enriched miRNA, miR-375, exert widespread control of alternative splicingin cancer cells by suppressing the RNA-binding proteinQuaking (QKI). During EMT, QKI-5 directly binds to and regulates hundreds of alternative splicingtargets and exerts pleiotropic effects, such as increasing cell migration and invasion and restraining tumour growth, without appreciably affecting mRNA levels. QKI-5 is both necessary and sufficient to direct EMT-associated alternative splicingchanges, and this splicingsignature is broadly conserved across many epithelial-derived cancer types. Importantly, several actin cytoskeleton-associated genes are directly targeted by both QKI and miR-200c, revealing coordinated control of alternative splicingand mRNA abundance during EMT These findings demonstrate the existence of a miR-200/ miR-375/QKI axis that impacts cancer-associated epithelial cell plasticity through widespread control of alternative splicing.