Histone Deacetylases (HDACs)

One of the most important classes of chromatin erasers associated with CM pathogenesis is HDACs, which catalyze the deletion of acetyl groups from histone tails [135]. At least 18 mammalian HDACs were identified and subdivided into four main classes, depending on their location and functional characteristics. Given the significant differences reported between the acetylation patterns of benign nevi and the malignant tissues of patients diagnosed with CM, it was thought that aberrant histone deacetylation could play important roles in the pathobiology of CM [136]. Subsequent studies with patientderived cell cultures have indeed shown that there is a loss of acetylation marks (H3K27Ac, H2BK5Ac, and H4K5Ac) and H3K4me2/3 during the transition from premalignant to the malignant phenotype, resulting in alterations of some essential signaling pathways in CM formation, including PI3K, interferon (IFN) -G, and TRAIL- and platelet-derived growth factor (PDGF) signaling [136].

Many other studies have shown that various HDACs are involved in skin tumorigenesis and can be exploited as biomarkers or therapeutic targets in melanomas. For instance, Wilmott et al. identified that increased expression of nuclear HDAC3 and cytoplasmic HDAC8 may serve as indicators of better prognosis in stage IV melanoma patients [35]. They also revealed an increase in HDAC8 levels in BRAF-mutant tumors [35]. Additionally, HDAC6 expression has recently been correlated with advanced stages and with an unfavorable prognosis [137]. In line with these observations, certain in vitro studies have shown that HDAC5 and HDAC6 are overexpressed in melanoma cell lines versus normal skin cells, being required for melanoma proliferation and metastasis through different signaling pathways [138]. Interestingly, HDAC6 inhibition inhibited tumor cell proliferation, and when knocked down cells were inoculated in animal models a decreased PD-L1 production and an augmented T-cell-mediated immune response was obtained [138].

Another epigenetic player investigated for its involvement in CM initiation is SIRT1 (class III HDAC proteins), which was found overexpressed in human melanoma cells and tissues in comparison to normal skin and melanocytes [139]. Further studies suggested that SIRT1 is upregulated in metastatic tumors compared to primary tumors, most likely due to its ability to support EMT programs via autophagic degradation of E-cadherin [140]. SIRT1, SIRT3 and SIRT6 were also proposed to support tumor growth in CM [141,142]. Interestingly, a recent study showed that dual inhibition of SIRT1 and SIRT3 mediated by 4 ′ -bromo-resveratrol inhibits melanoma cell proliferation and growth [143]. Thus, all this information suggests that pro-tumorigenic sirtuins have not only the value of prognosis biomarkers but also of potential therapeutic targets in CM and that inhibition of multiple sirtuins may be a promising strategy for improving clinical management of CM.
