Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies

Abstract

Cutaneous melanoma is a very aggressive neoplasia of melanocytic origin with constantly growing incidence and mortality rates world-wide. Epigenetic modifications (i.e., alterations of genomic DNA methylation patterns, of post-translational modifications of histones, and of microRNA profiles) have been recently identified as playing an important role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, cell signalling, differentiation, DNA repair, apoptosis, invasion and immune recognition. In this scenario, pharmacologic inhibition of DNA methyltransferases and/or of histone deacetylases were demonstrated to efficiently restore the expression of aberrantly-silenced genes, thus re-establishing pathway functions. In light of the pleiotropic activities of epigenetic drugs, their use alone or in combination therapies is being strongly suggested, and a particular clinical benefit might be expected from their synergistic activities with chemo-, radio-, and immuno-therapeutic approaches in melanoma patients. On this path, an important improvement would possibly derive from the development of new generation epigenetic drugs characterized by much reduced systemic toxicities, higher bioavailability, and more specific epigenetic effects.

Epigenetic regulation in human melanoma: past and future

“…17 Hypermethylation of specific tumor suppressor genes, including those involved in cell cycle regulation, cell signaling, transcription, DNA repair, and apoptosis, has been consistently reported in melanoma ( Table 1). 18,19 More recent studies have shown the methylation of gene bodies, and suggested that this correlates positively with transcription.…”

“…16 Characterization of epigenetic changes that initiate and promote human melanoma development may identify biomarkers that could be used for prevention, early detection, treatment, and monitoring of the progression of this malignancy. 17 …”

“…17 However, how the hypermethylated status of these genes contributes to the pathogenesis of melanoma remains largely unknown. Though gene transfer and RNA interference techniques are being employed to understand the roles of these genes, 18 no study to date has been able to establish a direct relation between the hypermethylated status of these genes and development of melanoma.…”

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

“…Among the pleiotropic activities of epigenetic drugs, 1 we have extensively characterized the immunomodulatory properties of DNA hypomethylating agents in human malignances of different histotype. 2,3 Exposure of neoplastic cells to these agents effectively improved T cell recognition of melanoma and renal carcinoma cells in vitro.…”

Immune-Therapy in Cutaneous Melanoma – Efficacy Immune Markers

“…In addition, an epigenetic profile should be concurrently self-perpetuating, heritable and reversible (Bonasio et al, 2010;Howell et al, 2009). It is now accepted that malignant transformation of melanocytes occurring in cutaneous melanoma, is greatly accompanied by epigenetic modifications (Sigalotti et al, 2010). Such "epimutations" could be turned on in defining new therapies considering the high incidence, poor prognosis and resistance of metastatic melanoma to conventional therapies (Howell et al, 2009).…”