H3K27 Methyltransferases (EZH2)

Histone lysine methyltransferase EZH2, responsible for H3K27 trimethylation, was also found to be dysregulated during the development of human melanomas. EZH2 is the catalytic subunit of the PRC2 complex and appears overexpressed in various tumors, including melanoma [121]. PRC2 trimethylates H3K27, orchestrating the repression of transcriptional programs [121]. Particularly for melanoma, PRC2 levels have been reported to increase gradually over the progression from benign nevi to malignant melanomas, suggesting that this protein plays a key role in CM initiation and progression [72]. Moreover, EZH2 and H3K27me3 are overexpressed in highly invasive melanoma cells and metastatic melanomas, leading to TSGs inactivation [72,76,121,122]. Finally, other studies have revealed that increased EZH2 levels are associated with poor prognosis in CM patients [123].

Regarding the roles played by EZH2 in the pathogenesis of CM, several mechanisms by which it supports tumor growth and metastasis have been proposed. Some authors have shown that EZH2 expression is associated with the suppression of senescence in human melanoma cells. For example, Fan at al. have shown that EZH2 can support unlimited melanocyte proliferation by repressing CDKN1A, which is not mediated by H3K27me3 deposition [124]. Conversely, EZH2 silencing inhibits cell proliferation, restoring senescent phenotype and p21/CDKN1A expression in a p53-independent manner. It was further observed that depletion of EZH2 removes HDAC1 from the transcriptional start site of CDKN1A, resulting in increased H3 acetylation and transcriptional activation. These observations confirm the existence of a synergistic relationship between EZH2, as part of PRC2 and HDAC, in mediating the suppression of certain senescence-related genes in melanoma cells [124]. In parallel, De Donatis at al. showed that EZH2 oncogenic activation is mediated by the non-canonical NF-kB signaling pathway; interestingly, NFkB2 silencing was associated with reconversion to the senescent phenotype, suggesting the pivotal roles of the NF-kB2/EZH2 axis in CM initiation and development [125]. Other studies have shown that induction of EZH2 in benign BrafV600E- or NrasQ61K-expressing melanocytes facilitates tumor metastasis and invasiveness by silencing genes relevant for cell surface organelle primary cilium integrity and by activating Wnt/β-catenin oncogenic signaling [77]. Finally, it is also worth mentioning that EZH2 gain-of-function mutations usually co-occur with BRAF V600E mutations in CM, promote aggressive cell morphologies and enhance melanoma tumor growth in vitro [126].
