Cancer is a disease consisting of both genetic and epigenetic changes. While increasing evidence demonstrates that tumour progression entails chromatin-mediated changes such as DNA methylation, the role of histone variants in cancer initiation and progression currently remains unclear. Here, we report that the histone variant macroH2A (mH2A) suppresses tumour progression of malignant melanoma. Loss of mH2A isoforms, histone variants generally associated with condensed chromatin and fine-tuning of developmental gene expression programs1-4, is positively correlated with increasing malignant phenotype of melanoma cells in culture and human tissue samples. Knockdown of mH2A isoforms in melanoma cells of low malignancy results in significantly increased proliferation and migration in vitro and growth and metastasis in vivo. Restored expression of mH2A isoforms rescues these malignant phenotypes in vitro and in vivo. We demonstrate that the tumour promoting function of mH2A loss is mediated, at least in part, through direct transcriptional up-regulation of CDK8. Suppression of CDK8, a colorectal cancer oncogene5, 6, inhibits proliferation of melanoma cells, and knockdown of CDK8 in cells depleted of mH2A suppresses the proliferative advantage induced by mH2A loss. Moreover, a significant inverse correlation between mH2A and CDK8 expression levels exists in melanoma patient samples. Taken together, our results demonstrate that mH2A is a critical component of chromatin that suppresses the development of malignant melanoma, a highly intractable cutaneous neoplasm.

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We report a rare case of multiple, co-exisitng verruciform xanthomas (VXs) of the anogenital region in the setting of cutaneous trauma. VX is a rare benign mucocutaneous neoplasm that typically presents as a solitary lesion with a predilection for the oral cavity, although extra-oral lesions have been reported involving the vulva, scrotum, penis, anal region and extremities. The etiology and pathogenesis of VX have yet to be determined; however, recent literature has reported that multifocal cutaneous VX are frequently associated with pre-existing inflammatory processes. A significant number of VXs of the skin have been found to co-exist with cutaneous disorders including graft vs. host disease, discoid lupus erythematosus, pemphigus vulgaris, and recessive dystrophic epidermolysis bullosa. Therefore, we speculate severe cutaneous trauma and chronic inflammation may induce epithelial keratinocytes to respond aberrantly leading to epidermal hyperplasia and foamy cell formation characterizing the VX lesion.