Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

• Published in: Clinical epigenetics 2020-08, Vol.12 (1), p.127, Article 127
• Main Authors: Azevedo, Hátylas, Pessoa, Guilherme Cavalcante, de Luna Vitorino, Francisca Nathália, Nsengimana, Jérémie, Newton-Bishop, Julia, Reis, Eduardo Moraes, da Cunha, Júlia Pinheiro Chagas, Jasiulionis, Miriam Galvonas
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Animal models; Animals; Autophagy; Breast cancer; Cell adhesion & migration; Cell cycle; Cell differentiation; Cell Line, Tumor; Cell lines; Cell migration; Deoxyribonucleic acid; Development and progression; Disease Models, Animal; Disease Progression; DNA; DNA binding proteins; DNA damage; DNA methylation; DNA repair; Endocytosis; Enzymes; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Epithelial-Mesenchymal Transition - genetics; Extracellular matrix; Gene expression; Gene Expression - genetics; Genes; Genetic research; Genetic transcription; Histone Code - genetics; Histones; Humans; Kinases; Light; Medical prognosis; Melanocytes; Melanoma; Melanoma - genetics; Melanoma - pathology; Mesenchyme; Metastases; Metastasis; Methylation; Methyltransferase; Mice; Neoplasm Metastasis - genetics; Phagocytosis; Stem cells; Telecommunication systems; Therapeutic targets; Transcription; Tumors; Ubiquitination
• ISSN: 1868-7075; 1868-7083; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-020-00910-9

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. 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. 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.