Current understanding of epigenetics role in melanoma treatment and resistance

Abstract

Melanoma is the most aggressive form of skin cancer resulting from genetic mutations in melanocytes. Several factors have been considered to be involved in melanoma progression, including genetic alteration, processes of damaged DNA repair, and changes in mechanisms of cell growth and proliferation. Epigenetics is the other factor with a crucial role in melanoma development. Epigenetic changes have become novel targets for treating patients suffering from melanoma. These changes can alter the expression of microRNAs and their interaction with target genes, which involves cell growth, differentiation, or even death. Given these circumstances, we conducted the present review to discuss the melanoma risk factors and represent the current knowledge about the factors related to its etiopathogenesis. Moreover, various epigenetic pathways, which are involved in melanoma progression, treatment, and chemo-resistance, as well as employed epigenetic factors as a solution to the problems, will be discussed in detail.

Keywords: Drug resistance; Epigenetics; Immunotherapy; Melanoma.

Fig. 1

HDACs remove acetyl groups from chromatins, which can be inhibited by HDACis. They act based on two strategies, including the direct inhibition of HDACs or indirect inhibition of HATs. Irrespective of strategy, HDACs are used to treat melanoma because they can induce various mechanisms leading to the prevention of tumor cells to develop, namely decreasing cyclins, AKT function, angiogenesis, and so forth. Additionally, HDACs increase autophagy, pro-apoptotic proteins, P21, ER stress, JNK activation, CD25, CD40, and CD80

Fig. 2

Histone lysine methyltransferases, namely KMT2D, EZH2, and SETDB1 can affect the advancement of melanoma cases. KMT2D can act as a regulator of IGFBP5 transcription to repress IGF1, thus inhibiting tumorigenesis. The SETDB1 can be triggered by Ret as a result of Src and PI3K pathway activation thenceforth, which affects AKT binding with SETDB1. This event leads to inhibiting pro-apoptotic genes such as Bim and Puma, and transcription blockade. EZH2 is involved in sundry signaling pathways such as Wnt/β-catenin, Ras, Notch, NF-KB, and β-adrenergic that deregulation of which can lead to tumorigenesis

Fig. 3

Some of the miRNAs affect migration, apoptosis, proliferation, and survival of melanoma cells via various mechanisms