title: NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2.
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.
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 12, Nice, France.
authors.forename: G M
authors.initials: GM
authors.lastname: De Donatis
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 12, Nice, France.
authors.forename: E
authors.initials: E
authors.lastname: Le Pape
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 12, Nice, France.
authors.forename: A
authors.initials: A
authors.lastname: Pierron
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, Nice, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Cheli
authors.affiliation: Human Biobank, Centre Hospitalier Universitaire de Nice, Nice, France.|Institute of Research on Cancer and Aging, IRCAN CNRS, Nice, France.
authors.forename: V
authors.initials: V
authors.lastname: Hofman
authors.affiliation: Human Biobank, Centre Hospitalier Universitaire de Nice, Nice, France.|Institute of Research on Cancer and Aging, IRCAN CNRS, Nice, France.
authors.forename: P
authors.initials: P
authors.lastname: Hofman
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, Nice, France.
authors.forename: M
authors.initials: M
authors.lastname: Allegra
authors.affiliation: Human Biobank, Centre Hospitalier Universitaire de Nice, Nice, France.|Institute of Research on Cancer and Aging, IRCAN CNRS, Nice, France.
authors.forename: K
authors.initials: K
authors.lastname: Zahaf
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, Nice, France.|Department of Dermatology, University Hospital of Nice, Nice, France.
authors.forename: P
authors.initials: P
authors.lastname: Bahadoran
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, Nice, France.
authors.forename: S
authors.initials: S
authors.lastname: Rocchi
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, Nice, France.
authors.forename: C
authors.initials: C
authors.lastname: Bertolotto
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 1, Nice, France.|Department of Dermatology, University Hospital of Nice, Nice, France.
authors.forename: R
authors.initials: R
authors.lastname: Ballotti
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 12, Nice, France.|Department of Dermatology, University Hospital of Nice, Nice, France.
authors.forename: T
authors.initials: T
authors.lastname: Passeron
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D052003:NF-kappa B p52 Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D052003:NF-kappa B p52 Subunit; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein