Search for novel therapeutic strategies by inhibiting histone modification enzymes targeting malignant traits of melanoma cells with different phenotypes

Abstract

Cutaneous melanoma emerges from the malignant transformation of the epidermis melanocytes and is considered the most severe amongst skin tumors due to its high risk of metastasis and therapeutic resistance. Since primary and metastatic melanomas carry, at least in part, the same set of driver mutations, epigenetic reprogramming appears to play an important role in tumor progression and heterogeneity. Epigenetic alterations are reversible covalent modifications that do not alter the nucleotide sequence of the DNA and show an important role in transcriptional regulation. Post-translational modifications of histones, DNA-associated proteins which organize chromatin, are one of the most studied epigenetic mechanisms, along with DNA methylation. Knowledge about epigenetic mechanisms involved in cellular plasticity still is poor. Previous data of our laboratory associate abundance patterns of different histone modifications and the expression of histone deacetylases (HDACs), methyltransferases (HMTs), and demethylases (HDMs) to distinct melanoma cellular phenotypes, mesenchymal/undifferentiated and differentiated/highly proliferative, of a linear cellular model of tumor progression. Studies which evaluate the use of inhibitors of histone-modifying enzymes are still scarce but have shown to be very promising, including when used in combination with other therapies. Treatment of melanoma cells presenting different phenotypes with HDACs, HMTs, and HDMs inhibitors will allow the evaluation of its effects in vitro on characteristics of death resistance, migration, invasion, and proliferation, and, in vivo on characteristics of tumor growth and metastasis formation. This study, which aims to identify effective drugs on the inhibition and/or elimination of phenotypically distinct melanoma cells, may contribute to the development of novel and more effective therapeutic strategies for melanoma. (AU)