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Activation of NF-κB by Akt upregulates Snail expression and induces epithelium mesenchyme transition

Oncogene volume 26, pages 7445–7456 (2007)Cite this article

Abstract

Carcinoma progression is associated with the loss of epithelial features, and the acquisition of mesenchymal characteristics and invasive properties by tumour cells. The loss of cell–cell contacts may be the first step of the epithelium mesenchyme transition (EMT) and involves the functional inactivation of the cell–cell adhesion molecule E-cadherin. Repression of E-cadherin expression by the transcription factor Snail is a central event during the loss of epithelial phenotype. Akt kinase activation is frequent in human carcinomas, and Akt regulates various cellular mechanisms including EMT. Here, we show that Snail activation and consequent repression of E-cadherin may depend on AKT-mediated nuclear factor-κB (NF-κB) activation, and that NF-κB induces Snail expression. Expression of the NF-κB subunit p65 is sufficient for EMT induction, validating this signalling module during EMT. NF-κB pathway activation is associated with tumour progression and metastasis of several human tumour types; E-cadherin acts as a metastasis suppressor protein. Thus, this signalling and transcriptional network linking AKT, NF-κB, Snail and E-cadherin during EMT is a potential target for antimetastatic therapeutics.

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Acknowledgements

We are grateful to John Burch (FCCC, Philadelphia, USA) and Danny Huylebroeck (University of Leuven, Laboratory of Molecular Biology (Celgen) for their constructive comments. We thank Manijeh Pasdar (U. Alberta, Edmonton, Canada) for the desmoplakin antibody, Robert Weil (Institut Pasteur) for YFP-p65 and all members of the GDM lab. SJ was supported by Ministère de la Recherche, Ligue Contre le Cancer (Comité de l'Essonne) and Société Française du Cancer. IP was supported by an Institut Curie fellowship and ARC. LL holds an INSERM position. This work was supported by the Ligue Nationale Contre le Cancer (Equipe Labellisée).

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  1. S Julien and I Puig: These authors contributed equally to this work.

Authors and Affiliations

  1. Developmental Genetics of Melanocytes, UMR 146 CNRS-Institut Curie, Bat. 110, Orsay Cedex, France

    S Julien, I Puig, J Bonaventure & L Larue

  2. Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    E Caretti & A Bellacosa

  3. Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology (Celgen), VIB7, University of Leuven, Leuven, Belgium

    L Nelles

  4. Department for Molecular Biomedical Research, VIB – Ghent University, Ghent, Belgium

    F van Roy

  5. Department biologie Cellulaire, Institut Jacques Monod, UMR 7592 CNRS, Universités Paris 6 et 7, 2 Place Jussieu, Tour 43, Paris Cedex 05, France

    C Dargemont

  6. Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigacio Medica, Universitat Pompeu Fabra, Barcelona, Spain

    A Garcia de Herreros

  7. Laboratory of Developmental Therapeutics, Istituto Regina Elena, Rome, Italy,

    A Bellacosa

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Correspondence to L Larue.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Julien, S., Puig, I., Caretti, E. et al. Activation of NF-κB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 26, 7445–7456 (2007). https://doi.org/10.1038/sj.onc.1210546

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