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

• Published in: EMBO reports Vol. 15; no. 12; pp. 1315 - 1329
• Main Authors: Knoll, Susanne, Fürst, Katharina, Kowtharapu, Bhavani, Schmitz, Ulf, Marquardt, Stephan, Wolkenhauer, Olaf, Martin, Hubert, Pützer, Brigitte M
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01.12.2014; Nature Publishing Group UK; Springer Nature B.V; BlackWell Publishing Ltd
• Subjects: Blotting, Western; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Chromatin Immunoprecipitation; E2F1 transcription factor; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; EMBO03; EMBO05; EMBO36; epithelial-mesenchymal transition; Epithelial-Mesenchymal Transition - genetics; Epithelial-Mesenchymal Transition - physiology; Fluorescent Antibody Technique; Humans; Immunohistochemistry; In Vitro Techniques; Medical research; Melanoma; Melanoma - metabolism; melanoma metastasis; Metastasis; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA cluster; Scientific Report; Skin cancer; thioredoxin-interacting protein; thioredoxin‐interacting protein; melanoma metastasis; miRNA cluster; E2F1 transcription factor; epithelial‐mesenchymal transition
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.201439392

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. Synopsis The E2F1‐miR‐244/452‐TXNIP pathway is shown to be crucial for melanoma invasion and metastasis in vivo . By activating the expression of miR‐224/452, E2F1 leads to the downregulation of its inhibitor, TXNIP, and induces EMT. In early primary tumors, high levels of TXNIP restrict E2F1 activity through p16 activation and subsequent inhibition of RB. Increasingly high levels of E2F1 during cancer progression lead to the transcriptional upregulation of the miR‐224/452 cluster. miR‐224 and miR‐452 repress the expression of TXNIP to induce E2F1‐dependent EMT and invasion. Graphical Abstract The E2F1‐miR‐244/452‐TXNIP pathway is shown to be crucial for melanoma invasion and metastasis in vivo . By activating the expression of miR‐224/452, E2F1 leads to the downregulation of its inhibitor, TXNIP, and induces EMT.