*4.2. Histone-Modifying Enzymes and PTMs in CM Development*

In addition to the undeniable role of DNA methylation in melanomagenesis, histone PTMs mediated by several writers, readers and erasers may also alter some transcriptional processes closely associated with CM initiation and progression [109].

The involvement of histone modifications in CM development has been suggested since benign nevi, which usually carry the BRAF V600E oncogenic mutation, rarely become melanoma, as this conversion requires additional events. Yet, valuable insights on the importance of histone-modifying enzymes and PTMs in melanomagenesis were obtained using zebrafish melanoma models [110]. Patton et al. developed the first experimental model of BRAF V600E driven melanoma using a zebrafish model expressing BRAF V600E under the control of the mitfa promoter in a p53 loss-of-function background [111]. Only a fraction of zebrafish developed melanocytic tumors, highlighting the existence of additional molecular events operating in concert with genetic alterations in melanoma. To examine these processes in more detail, the researchers developed a triple transgenic zebrafish model (p53/BRAF/crestin: EGFP), in which the crestin/EGFP gene marks neural crest stem and progenitor cells, from which melanocytes originate [111]. Melanocytic tumors reported in zebrafish models re-expressed crestin-EGFP gene, suggesting that these cancer cells are maintaining their neural crest identity. Notably, they identified enrichment of H3K27ac marks in super-enhancers at the sox10 locus, a major regulator of neural crest formation and melanomagenesis, suggesting that epigenetic regulation of SOX10 is an important step in melanoma initiation [111]. Later on, Scahill at al. revealed that loss of kdm2aa, an orthologue of KDM2A, triggered the spontaneous formation of melanomas at a high frequency in zebrafish [112]. These tumors were generated independently of BRAF V600E and other melanoma-related mutations in oncogenes and tumor suppressors. Finally, gene expression analysis revealed altered levels of genes involved in DNA replication, translation, and chromatin regulation after kdm2aa silencing, confirming on an alternative pathway that histone methylation may have vital roles in melanomagenesis [112].
