Re-establishment of 5-hmC landscape is capable of suppressing melanoma growth and improving the survival of the preclinical mice model.126 In addition to the general downregulation of 5-hmC content, focal DNA hyper-methylation of the promoters of some specific tumor suppressors has also been well illustrated in melanoma, in particular PTEN, P16INK4A, P14ARF, RASSF1A, and MGMT (occurring in ~60%, 30%, 80%, 55%, and 30% of melanomas, respectively)127–134 (Fig. 5), which is associated with functional deficiency of these genes during melanoma progression. This evidence concerns the gene CDKN2A and melanoma.