Histone Demethylases (HDMs)

The scientific progress made in recent years in deciphering the cancer epigenome has revealed the critical roles of histone H3 lysine 4 (H3K4) JARID1B/KDM5B demethylase in the tumorigenesis of various human tumors, including melanoma [144]. One of the pioneering studies in the field revealed that H3K4 demethylase JARID1B is overexpressed in melanocyte nevi and almost absent in melanoma samples [145]. However, subsequent studies have revealed increased heterogeneity of KDM5B in CM, and its expression levels have been documented to define distinct cellular states, even with antithetical effects on cellular tumor fate depending on the biological and clinical context [146]. KDM5B was found to mark a slow-cycling subpopulation of tumor cells which is essential for continuous tumor growth and resistance to therapy [147]. This population displays similar behaviors to that of cancer stem cells and give rise to a heterogeneous population of melanoma cells, being a major contributor to the increased heterogeneity observed in CM tumors [129]. Therefore, the assessment of KDM5B expression and H3K4 deposition patterns can provide valuable information about the clinical behavior of these tumors and may lead to more personalized therapies for CM patients.

H3K9me3 is an epigenetic mark of heterochromatin, which is often present on distal regions of genes [129]. H3K9 methyl groups may be erased by members of the lysinespecific histone demethylase (LSD) family. LSD1, often referred to as KDM1A, has the ability to demethylate histone 3 on lysine residues at position 4 (H3K4- gene promoter) and 9 (H3K9- distal) [129]. Interestingly, Yu et al. reported that oncogene-induced senescence of melanocytes relies on the deposition of H3K9me3 at the promoters of proliferationrelated genes [75]. This is in accordance with their findings highlighting that benign naevi displayed increased senescence-associated H3K9me3 levels, with almost no detectable activity of H3 lysine 9 demethylases LSD1 and Jumonji Domain-Containing Protein 2D (JMJD2C/KDM4C), whilst human melanoma tissues generally harbored increased expression of LSD1 and JMJD2C and reduced H3K9me3 reactivity [75]. To gain a broader understanding of the molecular mechanisms that are involved in this process, the authors induced the expression of LSD1 and JMJD2C in mouse and zebrafish models. It was further shown that these two enzymes cooperated to overcome the oncogenic Ras G12V/BRAF V600E-induced senescence by preventing H3K9me3 deposition at E2F target gene promoters, which further augmented melanomagenesis [75]. Of note, targeted inhibition of LSD1 and JMJD2C demethylases restored cellular senescence and growth arrest, potentiating LSD1 and JMJD2C regulation as a potential anti-cancer therapeutic strategy [75].
