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.

Figure 1

Epigenetic alterations in CM. Epigenetic regulation of gene expression involves the interplay of DNA methylation, histone modifications and miRNAs. A. Transcriptionally inactive genes (crossed red arrow) are characterized by the presence of methylated cytosines within CpG dinucleotides (grey circles), which is carried out and sustained by DNA methyltransferases (DNMT). Transcriptional repression may directly derive from methylated recognition sequence preventing the binding of transcription factors, or may be a consequence of the binding of methyl-CpG-binding proteins (MBP), which recruit chromatin remodelling co-repressor complexes. Transcriptionally active genes (green arrow) contain demethylated CpG dinucleotides (green circles), which prevent the binding of MBP and co-repressor complexes, and are occupied by complexes including transcription factors and co-activators. B. Histones are subjected to a variety of post-translational modifications on their amino terminus (N), including methylation and acetylation, which determine chromatin structure, resulting in the modulation of accessibility of DNA for the transcriptional machinery. The acetylation status of histones is controlled by the balanced action of histone acetyltransferases and histone deacetylases, and acetylated histones have been associated with actively expressed genes. Histone methylation may have both repressive (H3K9, H3K27) or promoting (H3K4) effects on transcription, depending on which residue is modified. C. MiRNAs are small non-coding RNAs that regulate the expression of complementary mRNAs. Once incorporated into the RNA-induced silencing complex, miRNAs recognize their target mRNA through a perfect or nearly perfect sequence complementarity, and direct their endonucleolytic cleavage or inhibit their translation. DICER, RNase III family endoribonuclease, ORF, open reading frame.

Figure 2

Selected pathways altered by DNA hypermethyation in CM. Aberrant promoter hypermethylation in CM may suppress the expression of APC, PTEN, RASSF1A, TMS1, TRAIL-R1, XAF1, and WIF1, leading to deregulation of different pathways, including apoptosis, cell cycle, cell-fate determination, cell growth, and inflammation. Gene symbol: APAF1, apoptotic peptidase activating factor 1; APC, adenomatous polyposis coli; BAX, BCL2-associated X protein; CYT C, cytochrome C; DIABLO, direct IAP-binding protein with low pI; DVL, dishevelled; FADD, Fas-associating protein with death domain; GF, Growth Factor; GSK3β, glycogen synthase kinase 3 beta; IL, interleukin; LRP, LDL receptor family; MOAP1, modulator of apoptosis 1; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide-3-kinase; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; RAR, retinoic acid receptor; RASSF1A, Ras association domain family 1; RTK, Receptor Tyrosine Kinase; TCF/LEF, T-cell factor/lymphoid enhancer factor; TMS1, Target Of Methylation Silencing 1; TRAIL, TNF-related apoptosis inducing ligand; TRAIL-R1, TRAIL receptor 1; WIF1, Wnt inhibitory factor 1; XAF1, XIAP associated factor 1; XIAP, X-linked inhibitor of apoptosis.