Despite recent advancements in therapy, melanoma still remains a highly lethal skin cancer.,A better understanding of the genetic and epigenetic changes responsible for melanoma formation and progression could result in development of more effective treatments.,Advanced melanomas are known to exhibit widespread promoter region CpG island methylation leading to inactivation of key tumor suppressor genes.,Meta-analyses of relevant microarray data sets revealed the hematopoietic stem cell regulator gene Latexin (LXN) to be commonly down regulated in approximately 50% of melanomas.,The CpG island in the promoter region of LXN was almost universally hypermethylated in melanoma cell lines and tumors and treatment of the cell lines with the demethylating drug, 5-Aza-2-deoxycytidine, resulted in increased LXN expression.,In this paper, we demonstrate that exogenous expression of LXN in melanoma cell lines results in a significant inhibition of tumor cell proliferation.,In addition, we show that the increased expression of LXN in these lines correlates with reduction in expression levels of stem cell transcription factors OCT4, NANOG, SOX2, KLF4 and MYCN indicating that LXN may exert its tumor suppressive function by altering the stem cell like properties of melanoma cells.
The clinical course of cutaneous melanoma (CM) can differ significantly for patients with identical stages of disease, defined clinico-pathologically, and no molecular markers differentiate patients with such a diverse prognosis.,This study aimed to define the prognostic value of whole genome DNA methylation profiles in stage III CM.,Genome-wide methylation profiles were evaluated by the Illumina Human Methylation 27 BeadChip assay in short-term neoplastic cell cultures from 45 stage IIIC CM patients.,Unsupervised K-means partitioning clustering was exploited to sort patients into 2 groups based on their methylation profiles.,Methylation patterns related to the discovered groups were determined using the nearest shrunken centroid classification algorithm.,The impact of genome-wide methylation patterns on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analyses.,Unsupervised K-means partitioning by whole genome methylation profiles identified classes with significantly different OS in stage IIIC CM patients.,Patients with a “favorable” methylation profile had increased OS (P = 0.001, log-rank = 10.2) by Kaplan-Meier analysis.,Median OS of stage IIIC patients with a “favorable” vs. “unfavorable” methylation profile were 31.5 and 10.4 months, respectively.,The 5 year OS for stage IIIC patients with a “favorable” methylation profile was 41.2% as compared to 0% for patients with an “unfavorable” methylation profile.,Among the variables examined by multivariate Cox regression analysis, classification defined by methylation profile was the only predictor of OS (Hazard Ratio = 2.41, for “unfavorable” methylation profile; 95% Confidence Interval: 1.02-5.70; P = 0.045).,A 17 gene methylation signature able to correctly assign prognosis (overall error rate = 0) in stage IIIC patients on the basis of distinct methylation-defined groups was also identified.,A discrete whole-genome methylation signature has been identified as molecular marker of prognosis for stage IIIC CM patients.,Its use in daily practice is foreseeable, and promises to refine the comprehensive clinical management of stage III CM patients.