miR‐200/375 control epithelial plasticity‐associated alternative splicing by repressing the RNA‐binding protein Quaking |
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| Authors: | B Kate Dredge Andrew G Bert Rachael Lumb Daniel P Neumann Xiaochun Li Simon J Conn Dawei Liu Cameron P Bracken David M Lawrence Nataly Stylianou Andreas W Schreiber Wayne D Tilley Brett G Hollier Yeesim Khew‐Goodall Luke A Selth Gregory J Goodall Philip A Gregory |
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| Institution: | 1. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia;2. Flinders Centre for Innovation in Cancer, College of Medicine & Public Health, Flinders University, Adelaide, SA, Australia;3. Discipline of Medicine, The University of Adelaide, Adelaide, SA, Australia;4. Institute of Health and Biomedical Innovation, Australian Prostate Cancer Research Centre ‐ Queensland, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Qld, Australia;5. Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia;6. Freemasons Foundation Centre for Men's Health, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia;7. School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, SA, Australia |
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| Abstract: | 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 by suppressing the RNA‐binding protein Quaking (QKI). During EMT, QKI‐5 directly binds to and regulates hundreds of alternative splicing targets 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 splicing changes, and this splicing signature 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 splicing and 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. |
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| Keywords: | alternative splicing epithelial– mesenchymal transition miR‐200 miR‐375 Quaking |
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