During embryonic development Wnt family members and bone morphogenetic proteins (BMPs) cooperatively induce epithelial-mesenchymal transition (EMT) in the neural crest.,Wnt and BMPs are reactivated during malignant transformation in melanoma.,We previously demonstrated that the BMP-antagonist noggin blocked the EMT phenotype of melanoma cells in the neural crest and malignant invasion of melanoma cells in the chick embryo; vice-versa, malignant invasion was induced in human melanocytes in vivo by pre-treatment with BMP-2.,Although there are conflicting results in the literature about the role of β-catenin for invasion of melanoma cells, we found Wnt/β-catenin signaling to be analogously important for the EMT-like phenotype of human metastatic melanoma cells in the neural crest and during invasion: β-catenin was frequently expressed at the invasive front of human primary melanomas and Wnt3a expression was inversely correlated with survival of melanoma patients.,Accordingly, cytoplasmic β-catenin levels were increased during invasion of melanoma cells in the rhombencephalon of the chick embryo.,Fibroblast derived Wnt3a reduced melanoma cell adhesion and enhanced migration, while the β-catenin inhibitor PKF115-584 increased adhesion and reduced migration in vitro and in the chick embryonic neural crest environment in vivo.,Similarly, knockdown of β-catenin impaired intradermal melanoma cell invasion and PKF115-584 efficiently reduced liver metastasis in a chick chorioallantoic membrane model.,Our observations were accompanied by specific alterations in gene expression which are linked to overall survival of melanoma patients.,We present a novel role for Wnt-signaling in neural crest like melanoma cell invasion and metastasis, stressing the crucial role of embryonic EMT-inducing neural crest signaling for the spreading of malignant melanoma.,The online version of this article (10.1186/s12943-018-0773-5) contains supplementary material, which is available to authorized users.
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.