MiR‐200/375 control epithelial plasticity‐associated alternative splicing by repressing the RNA‐binding protein Quaking. (6th June 2018)

• Record Type: Journal Article
• Authors: 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; Stylianou, Nataly; Schreiber, Andreas W; Tilley, Wayne D; Hollier, Brett G; Khew‐Goodall, Yeesim; Selth, Luke A; Goodall, Gregory J; Gregory, Philip A
• Is Part Of: EMBO journal. Volume 37:Number 13(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-06-06
• Subjects: alternative splicing -- epithelial–mesenchymal transition -- miR‐200 -- miR‐375 -- Quaking; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201899016
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: miR‐200 and miR‐375 regulate the level of the RNA‐binding protein, Quaking (QKI), which orchestrates widespread control of alternative splicing during epithelial‐mesenchymal transition (EMT), thereby affecting multiple facets of cancer‐associated epithelial cell plasticity. miR‐200c and miR‐375 control EMT‐associated alternative splicing by suppressing QKI. QKI‐5 influences cell plasticity, invasion and tumour growth by modulating alternative splicing. Actin cytoskeleton‐associated genes are targeted both by QKI and miR‐200c, revealing coordinated control of alternative splicing and mRNA abundance during EMT. Abstract : While miRNAs of the miR‐200 family are known to promote EMT and cancer progression via target mRNA repression, they exert a separate effect on epithelial cell plasticity by modulating alternative splicing signatures.