title: MicroRNA-200c represses migration and invasion of breast cancer cells by targeting actin-regulatory proteins FHOD1 and PPM1F.
abstract: MicroRNA-200c (miR-200c) has been shown to suppress epithelial-mesenchymal transition (EMT), which is attributed mainly to targeting of ZEB1/ZEB2, repressors of the cell-cell contact protein E-cadherin. Here we demonstrated that modulation of miR-200c in breast cancer cells regulates cell migration, cell elongation, and transforming growth factor β (TGF-β)-induced stress fiber formation by impacting the reorganization of cytoskeleton that is independent of the ZEB/E-cadherin axis. We identified FHOD1 and PPM1F, direct regulators of the actin cytoskeleton, as novel targets of miR-200c. Remarkably, expression levels of FHOD1 and PPM1F were inversely correlated with the level of miR-200c in breast cancer cell lines, breast cancer patient samples, and 58 cancer cell lines of various origins. Furthermore, individual knockdown/overexpression of these target genes phenocopied the effects of miR-200c overexpression/inhibition on cell elongation, stress fiber formation, migration, and invasion. Mechanistically, targeting of FHOD1 by miR-200c resulted in decreased expression and transcriptional activity of serum response factor (SRF), mediated by interference with the translocation of the SRF coactivator mycocardin-related transcription factor A (MRTF-A). This finally led to downregulation of the expression and phosphorylation of the SRF target myosin light chain 2 (MLC2) gene, required for stress fiber formation and contractility. Thus, miR-200c impacts on metastasis by regulating several EMT-related processes, including a novel mechanism involving the direct targeting of actin-regulatory proteins.
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jurmeister
authors.forename: Marek
authors.initials: M
authors.lastname: Baumann
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Balwierz
authors.forename: Ioanna
authors.initials: I
authors.lastname: Keklikoglou
authors.forename: Aoife
authors.initials: A
authors.lastname: Ward
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlmann
authors.forename: Jitao David
authors.initials: JD
authors.lastname: Zhang
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.forename: Özgür
authors.initials: Ö
authors.lastname: Sahin
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D024722:Cardiac Myosins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005326:Fetal Proteins / Q000378:metabolism*; D000080865:Formins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D018994:Myosin Light Chains / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D026362:Serum Response Factor / Q000096:biosynthesis; D022502:Stress Fibers / Q000378:metabolism; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C120021:FHOD1 protein, human; D005326:Fetal Proteins; D000080865:Formins; C533896:MIRN200 microRNA, human; C431575:MRTFA protein, human; D035683:MicroRNAs; D018994:Myosin Light Chains; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D026362:Serum Response Factor; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C107184:myosin light chain 2; C459194:PPM1F protein, human; D010749:Phosphoprotein Phosphatases; D024722:Cardiac Myosins