title: Cytoplasmic accumulation of NCoR in malignant melanoma: consequences of altered gene repression and prognostic significance.
abstract: Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy available in advanced stages. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer. In colorectal cancer cells, loss of nuclear NCoR is induced by Inhibitor of kappa B kinase (IKK) through the phosphorylation of specific serine residues. We here investigate whether NCoR function impacts in MM, which might have important diagnostic and prognostic significance. By IHC, we here determined the subcellular distribution of NCoR in a cohort of 63 primary invasive MM samples, and analyzed its possible correlation with specific clinical parameters. We therefore used a microarray-based strategy to determine global gene expression differences in samples with similar tumor stage, which differ in the presence of cytoplasmic or nuclear NCoR. We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression. Inhibition of IKK activity in melanoma cells reverts NCoR nuclear distribution and specific NCoR-regulated gene transcription. Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.
authors.affiliation: Dermatology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Gallardo
authors.affiliation: Pathology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.
authors.forename: Andreina
authors.initials: A
authors.lastname: Padrón
authors.affiliation: Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: Ricard
authors.initials: R
authors.lastname: Garcia-Carbonell
authors.affiliation: Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rius
authors.affiliation: Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: González-Perez
authors.affiliation: Pathology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Arumí-Uria
authors.affiliation: Pathology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.affiliation: Servei d'Anàlisi de Microarrays, Institut Hospital del Mar Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Nonell
authors.affiliation: Pathology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bellosillo
authors.affiliation: Dermatology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Segura
authors.affiliation: Dermatology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.
authors.forename: Ramon Maria
authors.initials: RM
authors.lastname: Pujol
authors.affiliation: Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.|Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Lopez-Bigas
authors.affiliation: Universitat de Vic, Universitat Central de Catalunya (UVic-UCC), Vic, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Bertran
authors.affiliation: Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.affiliation: Stem Cells and Cancer Research Laboratory, Institut Hospital del Mar Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Espinosa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*; D000096142:Cutaneous Malignant Melanoma
chemical_list: C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; C498143:RELA protein, human; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase
keywords: IKK; NCoR; gene transcription; melanoma progression
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