miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking
| Autor: | David M. Lawrence, Caroline A Phillips, Andreas W. Schreiber, Xiaochun Li, Wayne D. Tilley, Katherine A. Pillman, Luke A. Selth, John Toubia, Gregory J. Goodall, Daniel P. Neumann, Philip A. Gregory, Simon J. Conn, Suraya Roslan, Brett G. Hollier, Nataly Stylianou, B. Kate Dredge, Cameron P. Bracken, Dawei Liu, Rachael Lumb, Yeesim Khew-Goodall, Andrew G. Bert |
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| Přispěvatelé: | Pillman, Katherine A, Phillips, Caroline A, Roslan, Suraya, Toubia, John, Dredge, B Kate, Bert, Andrew G, Lumb, Rachael, Neumann, Daniel P, Li, Xiaochun, Conn, Simon J, Liu, Dawei, Bracken, Cameron P, Lawrence, David M, Schreiber, Andreas W, Khew-Goodall, Yeesim, Goodall, Greogory J, Gregory, Philip A |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition Cell Plasticity epithelial-mesenchymal transition RNA-binding protein Mice SCID Biology epithelial–mesenchymal transition General Biochemistry Genetics and Molecular Biology Article Madin Darby Canine Kidney Cells 03 medical and health sciences alternative splicing Quaking Dogs miR‐375 Cell Movement Cell Line Tumor microRNA Animals Humans Epithelial–mesenchymal transition Molecular Biology Gene Cancer Messenger RNA General Immunology and Microbiology General Neuroscience Alternative splicing RNA-Binding Proteins Articles miR-200 miR-375 RNA Biology Protein Quaking Cell biology MicroRNAs 030104 developmental biology miR‐200 RNA splicing Cell Adhesion Polarity & Cytoskeleton |
| Zdroj: | The EMBO Journal |
| ISSN: | 1460-2075 |
| Popis: | 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-200cand another epithelial-enriched miRNA, miR-375, exert wide spread 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 miR200/miR-375/QKI axis that impacts cancer-associated epithelial cell plasticity through widespread control of alternative splicing. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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