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NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2

Oncogene volume 35, pages 2735–2745 (2016)Cite this article

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A Corrigendum to this article was published on 26 May 2016

Abstract

Enhancer of Zeste homologue 2 (EZH2) belongs to the polycomb repressive complex 2 and catalyzes the methylation of histone H3 lysine 27. These pivotal epigenetic marks are altered in many cancers, including melanoma, as a result of EZH2 overexpression. Here, we show that the non-canonical-NF-kB pathway accounts for most of the NF-kB activity in melanoma cells, in contrast to non-cancer cells. We identify the non-canonical-NF-kB pathway as a key regulator of EZH2 expression in melanoma. We show a striking correlation between NF-kB2 and EZH2 expression in human melanoma metastases. We demonstrate that inhibition of the non-canonical NF-kB pathway by targeting NF-kB2/p52 or the upstream kinase NIK restores the senescence program in melanoma cells through the decrease of EZH2. On the contrary, the overexpression of NF-kB2/p52 in normal human melanocytes prevents stress- and oncogene-induced senescence. Finally, we show in mouse models that the inhibition of the non-canonical NF-kB pathway restores senescence and induces a dramatic reduction in tumor growth compared with controls, thus providing potential drug targets for the re-induction of senescence in melanoma and other cancers where EZH2 is overexpressed.

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Acknowledgements

This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Fondation ARC, and the Société Française de Recherche en Dermatologie (SRD). The authors would like to thank Professor Robert Weinberg from the MIT Ludiwig Center for Molecular Biology for kindly providing the Mel-ST cells.

Author contributions

ELP, GMDD and TP designed the experiments and wrote the manuscript; ELP and GMDD performed the majority of the experiments; AP performed the initial screening of drug activity in patients’ cells; YC performed the FACS measurement of the H3K9me3 levels; VH, KZ and PH performed the histology staining for melanoma; MA and PB isolated cells from the patients’ metastases and performed the mutational analysis; and SR, CB and RB provided reagents, helpful discussions and critical revisions for the manuscript.

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Authors and Affiliations

  1. INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 12, Nice, France

    G M De Donatis, E L Pape, A Pierron & T Passeron

  2. INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, Nice, France

    Y Cheli, M Allegra, P Bahadoran, S Rocchi, C Bertolotto & R Ballotti

  3. Human Biobank, Centre Hospitalier Universitaire de Nice, Nice, France

    V Hofman, P Hofman & K Zahaf

  4. Institute of Research on Cancer and Aging, IRCAN CNRS, Nice, France

    V Hofman, P Hofman & K Zahaf

  5. Department of Dermatology, University Hospital of Nice, Nice, France

    P Bahadoran, R Ballotti & T Passeron

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  1. G M De Donatis
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Correspondence to T Passeron.

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De Donatis, G., Pape, E., Pierron, A. et al. NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2. Oncogene 35, 2735–2745 (2016). https://doi.org/10.1038/onc.2015.331

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