Current Insights into Oral Cancer Epigenetics

Abstract

Epigenetic modifications have emerged into one of the cancer hallmarks, replacing the concept of malignant pathologies as being solely genetic-based conditions. The epigenetic landscape is responsible for normal development but also for the heterogeneity among tissues in terms of gene expression patterns. Dysregulation in these mechanisms has been associated with disease stage, and increased attention is now granted to cancer in order to take advantage of these modifications in terms of novel therapeutic strategies or diagnosis/prognosis tools. Oral cancer has also been subjected to epigenetic analysis with numerous studies revealing that the development and progression of this malignancy are partially induced by an altered epigenetic substrate together with genetic alterations and prolonged exposure to environmental risk factors. The present review summarizes the most important epigenetic modifications associated with oral cancer and also their potential to be used as new therapeutic targets.

Keywords: DNA methylation; epigenetics; histone; miRNA; non-coding RNAs; oral cancer.

Figure 1

The landscape of epigenetic mechanisms. Epigenetic changes consist of reversible modifications affecting the structure of the DNA/chromosome that are further translated at the protein level through expressional changes. One of the most studied epigenetic mechanisms consists of DNA methylation that occurs mainly within the CpG islands that are located in different repetitive genome regions or, more often, within promoter regions. The methylation pattern is different depending on the region, where most of the islands located in the promoter area are hypomethylated, the other ones, from repetitive segments, are methylated. Histone modifications are also part of the epigenetic machinery and mainly consist of ubiquitylation, sumoylation, methylation, acetylation, and also phosphorylation of the histone tails. Depending on the type of modification, these mechanisms can result in increased activity of the specific DNA segment or inversely blockage of function. Not in the least, miRNAs also play a crucial part in the establishment of the epigenetic landscape where these sequences are differentially expressed between different cellular entities and also between normal and pathological cells. Their ability to target and inhibit the translation of specific genes makes them crucial players within homeostatic signaling pathways and also therapeutic targets in disease states.

Figure 2

Epigenetic marks upon oral cancer. The evolution of oral cancer from a few altered cells to invasive phenotypes able to metastasize and populate secondary sites is the consequence of numerous factors that are interplaying their roles. Therefore, genetic events together with risk factors are combined with epigenetic mechanisms in order to ensure the proper environment for malignant development. All these factors gradually contribute to the organization of an unstable genome and also implicitly to the promotion of cancer advancement.