Background We have previously developed a murine cellular system that models the transformation from
melanocytes to metastatic
melanoma cells. This model was established by cycles of anchorage impediment of
melanocytes and consists of four
cell lines differentiated
melanocytes (
melan-a), pre-malignant
melanocytes (4C), malignant (4C11−), and
metastasis-prone (4C11+)
melanoma cells. Here, we searched for transcriptional and
epigenetic signatures associated with
melanoma progression and
metastasis by performing
a gene co-expression
analysis of
transcriptome data and a mass-
spectrometry-based profiling of
histone modifications in this model. Results Eighteen modules of co-expressed
genes were identified, and some of them were associated with
melanoma progression, epithelial-to-mesenchymal transition (EMT), and
metastasis. The
genes in these modules participate in
biological processes like
focal adhesion,
cell migration,
extracellular matrix organization,
endocytosis,
cell cycle,
DNA repair,
protein ubiquitination, and
autophagy. Modules and hub signatures related to EMT and
metastasis (turquoise, green yellow, and yellow) were significantly enriched in
genes associated to
patient survival in two independent
melanoma cohorts (TCGA and Leeds), suggesting they could be sources of novel prognostic
biomarkers. Clusters of
histone modifications were also linked to
melanoma progression, EMT, and
metastasis. Reduced levels of H4K5ac and H4K8ac marks were seen in the pre-malignant and tumorigenic
cell lines, whereas the
methylation patterns of H3K4, H3K56, and H4K20 were related to EMT. Moreover, the metastatic 4C11+
cell line showed higher H3K9me2 and H3K36me3
methylation, lower H3K18me1, H3K23me1, H3K79me2, and H3K36me2 marks and, in agreement,
downregulation of the H3K36me2
methyltransferase Nsd1. Conclusions We uncovered transcriptional and
histone modification signatures that may be molecular events driving
melanoma progression and
metastasis, which can
aid in the identification of novel prognostic
genes and
drug targets for treating the
disease.