title: E2F1 induces miR-224/452 expression to drive EMT through TXNIP downregulation.
abstract: Malignant melanoma is highly lethal due to its aggressive invasive properties and metastatic dissemination. The transcription factor E2F1 is crucial for melanoma progression through poorly understood mechanisms. Here, we show that the miR-224/miR-452 cluster is significantly increased in advanced melanoma and invasive/metastatic cell lines that express high levels of E2F1. miR-224/miR-452 expression is directly activated by E2F1 through transactivation of the GABRE gene. Ectopic expression of miR-224/miR-452 in less aggressive cells induces EMT and cytoskeletal rearrangements and enhances migration/invasion. Conversely, miR-224/miR-452 depletion in metastatic cells induces the reversal of EMT, inhibition of motility, loss of the invasive phenotype and an absence of lung metastases in mice. We identify the metastasis suppressor TXNIP as new target of miR-224/miR-452 that induces feedback inhibition of E2F1 and show that miR-224/452-mediated downregulation of TXNIP is essential for E2F1-induced EMT and invasion. The E2F1-miR-224/452-TXNIP axis constitutes a molecular signature that predicts patient survival and may help to set novel therapies.
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Knoll
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Fürst
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors.forename: Bhavani
authors.initials: B
authors.lastname: Kowtharapu
authors.affiliation: Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schmitz
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Marquardt
authors.affiliation: Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Wolkenhauer
authors.affiliation: Department of Neuropathology, University Hospital Charité, Berlin, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Martin
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany brigitte.puetzer@med.uni-rostock.de.
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Pützer
mesh_terms: D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008545:Melanoma / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C546140:MIRN224 microRNA, human; C574051:MIRN452 microRNA, human; D035683:MicroRNAs; C486715:TXNIP protein, human
keywords: E2F1 transcription factor; epithelial‐mesenchymal transition; melanoma metastasis; miRNA cluster; thioredoxin‐interacting protein