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EMBO Rep. 2014 Dec;15(12):1315-29. doi: 10.15252/embr.201439392. Epub 2014 Oct 23.

E2F1 induces miR-224/452 expression to drive EMT through TXNIP downregulation.

Author information

1
Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
2
Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
3
Department of Neuropathology, University Hospital Charité, Berlin, Germany.
4
Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany brigitte.puetzer@med.uni-rostock.de.

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.

KEYWORDS:

E2F1 transcription factor; epithelial‐mesenchymal transition; melanoma metastasis; miRNA cluster; thioredoxin‐interacting protein

PMID:
25341426
PMCID:
PMC4264934
DOI:
10.15252/embr.201439392
[Indexed for MEDLINE]
Free PMC Article

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