Abstract
Epigenetic alterations have emerged as essential contributors in the pathogenesis of various human diseases, including cutaneous melanoma (CM). Unlike genetic changes, epigenetic modifications are highly dynamic and reversible and thus easy to regulate. Here, we present a comprehensive review of the latest research findings on the role of genetic and epigenetic alterations in CM initiation and development. We believe that a better understanding of how aberrant DNA methylation and histone modifications, along with other molecular processes, affect the genesis and clinical behavior of CM can provide the clinical management of this disease a wide range of diagnostic and prognostic biomarkers, as well as potential therapeutic targets that can be used to prevent or abrogate drug resistance. We will also approach the modalities by which these epigenetic alterations can be used to customize the therapeutic algorithms in CM, the current status of epi-therapies, and the preliminary results of epigenetic and traditional combinatorial pharmacological approaches in this fatal disease.
Highlights
Cutaneous melanoma (CM) is an aggressive neoplasm that evolves from the malignant transformation of neural crest stem cell-derived melanocytes [1]
The remarkable progress made in recent years in deciphering CM biology has resulted in the development of several targeted therapies and immune-checkpoint inhibitors (ICIs), such as anti-programmed death (PD-1) and anti-cytotoxic T lymphocyte antigen (CTLA-4), that have truly revolutionized metastatic CM treatment
The progress made in understanding them led to the development of DNA methyltransferase inhibitors (DNMTIs) and histone deacetylase inhibitors (HDACi), which constitute the first generation of epigenetic inhibitors [39]
Summary
Cutaneous melanoma (CM) is an aggressive neoplasm that evolves from the malignant transformation of neural crest stem cell-derived melanocytes [1]. Epigenetic alterations are usually pro-tumorigenic, facilitating the suppression of tumor suppressor genes and the activation of oncogenes These reversible changes may help tumors escape the immune response by reducing the expression of genes involved in the antigen processing and presentation or viral defense pathways. In line with these observations, myeloid-derived suppressor cells (MDSCs) may differentiate into tumor-associated macrophages (TAMs) or interfere with T cell activity, promoting tumorigenesis as transcription factors induce alternative transcriptional programs resulting in epigenetic alterations [80]. Inactivation of tumor suppressor genes (TSGs) due to specific DNA methylation in the promoter regions was the first epigenetic alteration studied in CM more than 10 years ago [87] (Figure 1). All this information supports the further development of 5-hmC IHC expression as a prognostic biomarker that can add some precision to the American Joint Committee on Cancer (AJCC) staging system [108]
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