Cytoplasmic accumulation of NCoR in malignant melanoma: consequences of altered gene repression and prognostic significance

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.

[1]  M. Kris,et al.  Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis , 2014, Cell.

[2]  Michael P. Schroeder,et al.  IntOGen-mutations identifies cancer drivers across tumor types , 2013, Nature Methods.

[3]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[4]  S. Thiyagarajan,et al.  MAGE-C2 promotes growth and tumorigenicity of melanoma cells, phosphorylation of KAP1, and DNA damage repair. , 2013, The Journal of investigative dermatology.

[5]  G. Pawelec,et al.  Hsps are up-regulated in melanoma tissue and correlate with patient clinical parameters , 2013, Cell Stress and Chaperones.

[6]  A. Gonzalez-Perez,et al.  Functional impact bias reveals cancer drivers , 2012, Nucleic acids research.

[7]  D. Bernstein,et al.  SERPINE1 expression discriminates site‐specific metastasis in human melanoma , 2012, Experimental dermatology.

[8]  Syed Haider,et al.  International Cancer Genome Consortium Data Portal—a one-stop shop for cancer genomics data , 2011, Database J. Biol. Databases Curation.

[9]  C. Sander,et al.  Predicting the functional impact of protein mutations: application to cancer genomics , 2011, Nucleic acids research.

[10]  M. Bar‐eli,et al.  Expression of Id-1 is regulated by MCAM/MUC18: a missing link in melanoma progression. , 2011, Cancer research.

[11]  D. Speicher,et al.  IL8 and Cathepsin B as Melanoma Serum Biomarkers , 2011, International journal of molecular sciences.

[12]  Laurent Gil,et al.  Ensembl variation resources , 2010, BMC Genomics.

[13]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[14]  I. Fariñas,et al.  Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone , 2009, Nature Neuroscience.

[15]  W. Leenders,et al.  Semaphorin 3E expression correlates inversely with Plexin D1 during tumor progression. , 2008, The American journal of pathology.

[16]  J. Flores,et al.  The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. , 2008, Cancer cell.

[17]  P. Guldberg,et al.  The genome and epigenome of malignant melanoma , 2007, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[18]  G. Capellá,et al.  Aberrant Cytoplasmic Localization of N-CoR in Colorectal Tumors , 2007, Cell cycle.

[19]  F. Real,et al.  Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer , 2007, Proceedings of the National Academy of Sciences.

[20]  A. Richmond,et al.  NF‐κB activation in melanoma , 2006 .

[21]  Jianxiang Wang,et al.  Nuclear receptor co‐repressor gene localizes to 17p11.2, a frequently deleted band in malignant disorders , 1999, Genes, chromosomes & cancer.

[22]  A. Richmond,et al.  Enhanced Degradation of I-κBα Contributes to Endogenous Activation of NF-κB in Hs294T Melanoma Cells , 1997 .

[23]  A. Eggermont,et al.  Differential TIMP3 expression affects tumor progression and angiogenesis in melanomas through regulation of directionally persistent endothelial cell migration , 2013, Angiogenesis.

[24]  S. Henikoff,et al.  Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm , 2009, Nature Protocols.

[25]  A. Richmond,et al.  NF-kappaB activation in melanoma. , 2006, Pigment cell research.

[26]  A. Richmond,et al.  Enhanced degradation of I-kappaB alpha contributes to endogenous activation of NF-kappaB in Hs294T melanoma cells. , 1997, Cancer research.