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

Abstract

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.

Bioinformatics analysis based on ferroptosis-related lncRNAs: construction of a clinical prognostic model for nasopharyngeal carcinoma and correlation analysis

“…The results showed that ferroptosis inhibited the growth of malignant nasopharyngeal carcinoma cells, and the mechanism was related to DNA damage. Most of the current studies regulate cell ferroptosis progression by regulating the accumulation of lipid ROS and iron metabolism (31)(32)(33). Meanwhile, stabilizing the intracellular GSH concentration also protects cells from the lipid peroxidation reaction and subsequently suppresses the ferroptosis process (34).…”

Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma

“…Alterations in histone “writers” or “erasers” have been associated with many pathologies, including cancer [ 31 , 45 , 67 ]. Histone modifications can be associated in CM with therapy resistance [ 68 ] and/or with epithelial–mesenchymal transition (EMT) and metastasis [ 69 ].…”

G9a: An Emerging Epigenetic Target for Melanoma Therapy

“…Overexpression of G9a promotes upregulation of Notch1 signaling pathway Melanoma [27] Elevated Notch signaling associated with treatment resistance and more invasive phenotypes Melanoma [28][29][30] Notch signaling in fibroblasts creates a less favorable microenvironment Melanoma [32,33] G9a levels increase in NICD-induced model of bile duct cancer Cholangiocarcinoma [31] Metastasis H3K9me2 is increased between non-metastatic mesenchymal-like to metastatic melanoma cells Melanoma [34] HOX genes are upregulated in metastatic melanoma Melanoma [35] HOXA1 is a repressed target of G9a Glioblastoma [36] G9a represses CDH10 increasing cellular motility during hypoxia Breast Cancer [37] Autophagy G9a inhibition activates autophagy Melanoma [38] G9a represses MAP1LC3B and blocks autophagy Glioblastoma [39,40] G9a vacates autophagy related gene promoters under starvation in vitro Cervical and Pancreatic Cancer [41] G9a blocks autophagy through activation of mTOR Gastric Cancer [42] G9a has also been linked to tumor growth and metastasis. In vitro studies using serial detachment and re-adhesion of Melan-A cells also found that H3K9me2 increased between non-metastatic mesenchymal-like melanoma cells, compared to the metastatic cells [34]. The detachment and re-adhesion of cells on a plate is a highly artificial model of epithelial-to-mesenchymal transition, but additional evidence for a role of G9a in melanoma metastasis can be found in other tumor types.…”

“…G9a has also been linked to tumor growth and metastasis. In vitro studies using serial detachment and re-adhesion of Melan-A cells also found that H3K9me2 increased between non-metastatic mesenchymal-like melanoma cells, compared to the metastatic cells [ 34 ]. The detachment and re-adhesion of cells on a plate is a highly artificial model of epithelial-to-mesenchymal transition, but additional evidence for a role of G9a in melanoma metastasis can be found in other tumor types.…”