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• W2140547887 abstract "Mutations in the CYLD gene constitute the molecular basis for a group of autosomal dominant inherited diseases characterized by the development of numerous benign epithelial tumors of adnexal differentiation. Patients with multiple familial trichoepithelioma are predisposed to trichoepitheliomas, patients with familial cylindromatosis develop multiple cylindromas, and patients with Brooke–Spiegler syndrome feature both tumors in combination with spiradenomas. Occasionally, malignant transformation occurs, usually with the features of a cylindrocarcinoma. CYLD exhibits the characteristics of a tumor suppressor gene, and loss of heterocygosity was demonstrated in cylindromas. Most of the mutations found in CYLD result in premature protein truncations. CYLD encodes for a cytoplasmic protein with three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains and a catalytic domain with ubiquitin carboxy-terminal hydrolase activity responsible for removal of both lysine 48 and 63 linked polyubiquitin chains. Targets of CYLD include NFκB-essential modulator (NEMO), TNF-receptor-associated factors (TRAFs), and B-cell lymphoma 3 (Bcl3), resulting in inhibition of nuclear factor κ B (NF-κB) signaling. Besides, CYLD activity abrogates the ubiquitylation-dependent nuclear translocation of BCL3 following phorbol ester or UV treatment, thereby preventing the up-regulation of cyclin D1 and induction of cell growth. Reduction or even loss of CYLD expression has also been found in spontaneously arising adnexal tumors as well as in several solid human tumors of epithelial origin such as cervix, kidney, colon, and liver cancer (Massoumi and Paus, 2007). Massoumi et al. now implicate CYLD in the pathogenesis of a tumor of an entirely different lineage, malignant melanoma. They found reduction of CYLD mRNA and protein in several human melanoma cell lines, freshly isolated human melanoma cells as well as in primary melanomas and melanoma metastases. Absence of promoter methylation or CYLD mutations suggested down-regulation at the transcriptional level. Three potential binding sites for the transcriptional repressor Snail1 were identified in the CYLD promoter and confirmed by chromatin immunoprecipitation. Snail1 transcription factors are involved in epithelial mesenchymal transition, and have been identified as drivers of the progression and invasiveness of several tumors. The first E-box element in the CYLD promoter was identified as a binding site for Snail1 by reporter gene assays. Depletion of Snail1 by si-RNAs or by antisense DNA led to a strong up-regulation of CYLD protein in melanoma cells. Snail expression was activated by ERK/mitogen-activated protein kinase (MAPK) signaling. Constitutive activation of the BRAF kinase by a V600E mutation is one of the most common abnormalities found in melanoma (Lopez-Bergami et al., 2008), and intriguingly, overexpression of BRAF V600E resulted in up-regulation of Snail1 and down-regulation of CYLD. Phenotypically, suppression of Snail resulted in impaired proliferation and migration, and this response was almost completely reversed when CYLD was depleted as well. When xenografted into nude mice, antisense Snail clones formed smaller tumors than controls. Conversely, CYLD depletion reconstituted this growth impairment and resulted in a more invasive growth pattern. A possible explanation for this altered growth behavior is offered by identifying N-cadherin and cyclin D1 as potential targets of repression by CYLD. The mainly nuclear localization of the BCL3 transcriptional co-activator in melanoma cells was abolished by ectopic expression of CYLD. CYLD also reduced the expression of cyclin D1, a known positive regulator of cell cycle progression. CYLD expression also impaired the expression of N-cadherin. A switch from expression of the epithelial E-cadherin to N-cadherin is frequently observed at the transition to invasiveness and metastasis. Interestingly, both the cyclin D1 and the N-cadherin genes harbor NF-κB binding sites. Forced expression of N-cadherin reversed the CYLD-mediated reduction in melanoma motility and invasiveness. In summary, these data support a model (Figure 1) according to which constitutively active BRAF activates the ERK/MAPK pathway, leading to increased Snail1 expression and subsequent repression of the CYLD promoter. BCL3 is no longer de-ubiquitylated by CYLD and accumulates increasingly in the nucleus, where it activates the NF-κB-dependent transcription of cyclin D1 and N-cadherin. The authors finally extend the relevance of their findings to the clinic by correlating loss of CYLD expression with increased melanoma invasion level, tumor thickness, and a decrease in progression-free survival. Conversely, CYLD expression in primary melanomas appears to be a positive prognostic marker. Fitting the overall model, Snail expression showed the opposite pattern of correlation with melanoma grade and prognosis. Pathway of BRAF-induced cell proliferation and migration involving activation of Snail1 and downregulation of CYLD. Where do these findings put CYLD and Snail1 in the multi-step process from melanocytic atypia to radial growth phase melanoma, invasion, and metastasis? It is unlikely that CYLD plays a role in early melanomagenesis, as patients with the above-mentioned CYLD-deficient tumor susceptibility syndromes typically do not develop melanoma. Presumably, CYLD down-regulation in melanoma confers a growth advantage to tumors arising from other molecular defects. It would be interesting to see whether the highly prevalent V600E mutations in BRAF in benign melanocytic nevi also lead to Snail activation, CYLD suppression, and subsequent increases in cyclin D1 and N-cadherin. Further studies will have to determine whether the prognostically more favorable CYLD-positive primary melanomas define a distinct subset of melanoma maintaining CYLD expression up to the metastatic stage, or whether all melanomas ultimately down-regulate CYLD expression. Apart from stimulating proliferation and invasiveness, down-regulation of CYLD might provide additional advantages to the tumor. Only recently, down-regulation of CYLD by the human papilloma virus E6 protein has been linked to the NF-κB-mediated hypoxia-resistance of squamous cell carcinomas. Previous studies have failed to link melanoma hypoxia resistance to the NF-κB pathway." @default.
• W2140547887 created "2016-06-24" @default.
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• W2140547887 date "2009-03-11" @default.
• W2140547887 modified "2023-10-16" @default.
• W2140547887 title "Snail puts melanoma on the fast track" @default.
• W2140547887 cites W1992217193 @default.
• W2140547887 cites W2058409986 @default.
• W2140547887 doi "https://doi.org/10.1111/j.1755-148x.2009.00552.x" @default.
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