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

De Donatis GM, Pape EL, Pierron A, Cheli Y, Hofman V, Hofman P, Allegra M, Zahaf K, Bahadoran P, Rocchi S, Bertolotto C, Ballotti R, Passeron T

Oncogene 2015 Sep;

Abstract

PMID: 26364600

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.Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.331.