NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2
| Autor: | Katia Zahaf, G.-M. De Donatis, Stéphane Rocchi, Yann Cheli, Thierry Passeron, Maryline Allegra, Philippe Bahadoran, Robert Ballotti, A Pierron, Corine Bertolotto, E Le Pape, V Hofman, Paul Hofman |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Senescence Transcriptional Activation Cancer Research Down-Regulation Mice Nude macromolecular substances Biology 03 medical and health sciences Histone H3 Mice NF-kappa B p52 Subunit Cell Line Tumor medicine Genetics Animals Humans Enhancer of Zeste Homolog 2 Protein Epigenetics Enhancer Molecular Biology Melanoma Kinase EZH2 medicine.disease 030104 developmental biology Cell culture Cancer research Heterografts |
| Zdroj: | Oncogene. 35(21) |
| ISSN: | 1476-5594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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