miR-200 and miR-375 control widespread epithelial plasticity-associated alternative splicing by controlling Quaking

Members of the miR-200 family are critical gatekeepers of 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 splicing in cancer cells. This is achieved by strong suppression of the RNA binding protein Quaking (QKI). QKI directly regulates hundreds of EMT alternative splicing events converging on targets within the actin cytoskeleton regulatory network without appreciably affecting mRNA levels, resulting in pleiotropic effects such as increased cell migration and invasion. QKI-driven alternative splicing signatures are broadly conserved across many cancer types. Importantly, actin-associated genes are directly targeted by both miR-200c/miR-375 and QKI, revealing coordinated control of mRNA abundance and alternative splicing during EMT. These findings demonstrate the existence of a miR-200/miR-375/QKI axis that controls alternative splicing and critically impacts on cancer-associated epithelial cell plasticity.