DOT1L and melanoma: SETDB1 is responsible for the methylation of histone H3 on lysine 9 (H3K9) and is recurrently amplified in melanoma to play an oncogenic role.159,160 Metabolic reprogramming endows melanoma cells with increased histone H3 trimethylation and paralleled higher metastatic capacity that can be reversed by the pharmacological inhibition of SETDB1.161 Different from SETDB1, DOT1L gene is located in a frequently deleted region and undergoes somatic mutation that compromises its methyltransferase enzyme activity which leads to reduced H3K79 methylation.