Melanoma epigenetics: novel mechanisms, markers, and medicines

Abstract

The incidence and mortality rates of cutaneous melanoma continue to increase worldwide, despite the deployment of targeted therapies. Recently, there has been rapid growth and development in our understanding of epigenetic mechanisms and their role in cancer pathobiology. Epigenetics--defined as the processes resulting in heritable changes in gene expression beyond those caused by alterations in the DNA sequence--likely contain the information that encodes for such phenotypic variation between individuals with identical genotypes. By altering the structure of chromatin through covalent modification of DNA bases or histone proteins, or by regulating mRNA translation through non-coding RNAs, the epigenome ultimately determines which genes are expressed and which are kept silent. While our understanding of epigenetic mechanisms is growing at a rapid pace, the field of melanoma epigenomics still remains in its infancy. In this Pathology in Focus, we will briefly review the basics of epigenetics to contextualize and critically examine the existing literature using melanoma as a cancer paradigm. Our understanding of how dysregulated DNA methylation and DNA demethylation/hydroxymethylation, histone modification, and non-coding RNAs affect cancer pathogenesis and melanoma virulence, in particular, provides us with an ever-expanding repertoire of potential diagnostic biomarkers, therapeutic targets, and novel pathogenic mechanisms. The evidence reviewed herein indicates the critical role of epigenetic mechanisms in melanoma pathobiology and provides evidence for future targets in the development of next-generation biomarkers and therapeutics.

Figure 1

Summary of the three primary epigenetic mechanisms. (1) DNA methylation. (2) Histone post-translational modifications. (3) RNA-based mechanisms, including miRNAs and lncRNAs. Note: this diagram does not illustrate its mechanisms of binding and silencing mRNAs. From Matouk and Marsden (2008), reprinted with permission from Lippincott Williams & Wilkins.

Figure 2

The pathway involved in the TET-dependent generation of 5-hmC, an epigenetic mark that is lost from the melanoma genome (pictorially rendered to lower right).

Figure 3

Increasingly ‘dysplastic’ melanocytic lesions show progressive loss of immunohistochemical staining for 5-hydroxymethylcytosine. Immunohistochemical staining with anti-5-hydroxymethylcytosine (5-hmC demonstrates progressive loss of 5-hmC with progression from benign nevus (no dysplasia) to low and high grade dysplastic nevi, and finally to melanoma. Sections at x200 are shown above with selected areas that are further magnified in the panels directly below. From Larson et al. (2014), reprinted with permission from Nature Publishing Group.

Figure 4

Schematic representation of potential interplay between epigenetics (loss of 5-hmC) and melanoma stem cell (MSC) expression during melanoma progression. Melanomagenesis may originate in “normal skin”, or in a pre-exiting benign or dysplastic nevus as a result of transformation of melanocytes/nevus cells, a process that appears to be associated with progressive loss of 5-hmC and concomitant heightened activity of self-renewing, stem-like cells. Intravasation of primary melanoma as a consequence of dermal invasion transports cells epigenetically programmed for malignant behavior to lymph nodes and vital organs. Experimental models of metastases reveal cells expressing MSC markers to be relatively devoid of 5-hmC, consistent with epigenetic interplay with the stem cell component of the tumor at the metastatic site. (Lung diagram adapted courtesy of Patrick J. Lynch, medical illustrator; C. Carl Jaffe, MD, cardiologist. http://creativecommons.org/licenses/by/2.5/).