Malignant melanoma is the most deadly form of skin cancer.,It originates from melanocytic cells and can also arise at other body sites.,Early diagnosis and appropriate medical care offer excellent prognosis with up to 5-year survival rate in more than 95% of all patients.,However, long-term survival rate for metastatic melanoma patients remains at only 5%.,Indeed, malignant melanoma is known for its notorious resistance to most current therapies and is characterized by both genetic and epigenetic alterations.,In cutaneous melanoma (CM), genetic alterations have been implicated in drug resistance, yet the main cause of this resistance seems to be non-genetic in nature with a change in transcription programs within cell subpopulations.,This change can adapt and escape targeted therapy and immunotherapy cytotoxic effects favoring relapse.,Because they are reversible in nature, epigenetic changes are a growing focus in cancer research aiming to prevent or revert the drug resistance with current therapies.,As such, the field of epigenetic therapeutics is among the most active area of preclinical and clinical research with effects of many classes of epigenetic drugs being investigated.,Here, we review the multiplicity of epigenetic alterations, mainly histone alterations and chromatin remodeling in both cutaneous and uveal melanomas, opening opportunities for further research in the field and providing clues to specifically control these modifications.,We also discuss how epigenetic dysregulations may be exploited to achieve clinical benefits for the patients, the limitations of these therapies, and recent data exploring this potential through combinatorial epigenetic and traditional therapeutic approaches.
Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma.,To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma.,Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2.,Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS), we subsequently determined using tissue microarray (TMA) analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes.,To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT) 1 and 4.,Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma.,Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS.,Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy.