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Review
. 2016:945:151-172.
doi: 10.1007/978-3-319-43624-1_7.

The Role of DNA Methylation in Cancer

Ranjani Lakshminarasimhan  1 , Gangning Liang  2
Affiliations
Review

The Role of DNA Methylation in Cancer

Ranjani Lakshminarasimhan et al. Adv Exp Med Biol. 2016.

Abstract

The malignant transformation of normal cells is driven by both genetic and epigenetic changes. With the advent of next-generation sequencing and large-scale multinational consortium studies, it has become possible to profile the genomes and epigenomes of thousands of primary tumors from nearly every cancer type. From these genome-wide studies, it became clear that the dynamic regulation of DNA methylation is a critical epigenetic mechanism of cancer initiation, maintenance, and progression. Proper control of DNA methylation is not only crucial for regulating gene transcription, but its broader consequences include maintaining the integrity of the genome and modulating immune response. Here, we describe the aberrant DNA methylation changes that take place in cancer and how they contribute to the disease phenotype. Further, we highlight potential clinical implications of these changes in the context of prognostic and diagnostic biomarkers, as well as therapeutic targets.

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Figures

Fig. 1
Fig. 1
DNA methylation equilibrium between the promoter and gene body modulates gene expression. In this diagram, methylated CpG sites are represented by red circles, unmethylated CpG sites are represented by white circles, and green arrows are indicative of active expression, while red arrow marks the absence of expression. (a) In normal mammalian tissue, genes that are actively transcribed have unmethylated promoters and some methylation in the gene body. (b) With the onset of cancer, however, promoter hypermethylation can turn off the expression of genes, and gene body hypermethylation can permit a more robust expression of some genes. (c) Treatment with DNA methyltransferase inhibitors such as 5-Aza-CdR can restore gene expression by removing aberrant methylation
Fig. 2
Fig. 2
DNMTi exert antitumoral effect by eliciting immune response in cancer cells. Treatment with DNA methyltransferase inhibitors induces transcription of endogenous retroviral (ERV) elements. These double-stranded RNAs are recognized by viral recognition proteins such as RIG1 and MDA5, which in turn interact with the mitochondrial antiviral signaling (MAVS) proteins. MAVS-mediated IRF7 activation leads to the translocation of IRF7 from the cytoplasm to the nucleus where it initiates transcription of interferons (IFNs) and interferon-stimulated genes (ISGs), which then contribute to reduced proliferation (Modified from Chiappinelli et al. 2015; Licht 2015; Roulois et al. 2015)
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