Chapter 7 - Methylation of DNA in Cancer

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1. Abstract

Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. Methylation of cytosine bases in DNA provides a layer of epigenetic control in many eukaryotes that has important implications for normal biology and disease. DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting, and chromosome stability. Consistent with these important roles, a growing number of human diseases including cancer have been found to be associated with aberrant DNA methylation. Recent advancements in the rapidly evolving field of cancer epigenetics have described extensive reprogramming of every component of the epigenetic machinery in cancer, such as DNA demethylation. Hypomethylation of the genome largely affects the intergenic and intronic regions of the DNA, particularly repeat sequences and transposable elements, and it is believed to result in chromosomal instability and increased mutation events. Therefore, we propose that R/G-chromosome band boundaries, which correspond with the early/late-switch regions of replication timing and a transition in relative GC content, correspond to ā€œunstableā€ genomic regions in which concentrated occurrences of repetitive sequences and transposable elements including LINE and Alu elements are hypomethylated during tumorigenesis.

In this review, we discuss the current understanding of alterations in DNA methylation composing the epigenetic landscape that occurs in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, and the potential use of this knowledge in designing more effective treatment strategies.

Section snippets

Introduction: DNA Methylation and Epigenetic Modification

Together with other epigenetic modifications such as histone acetylation, DNA methylation provides a stable gene silencing mechanism by physically blocking gene expression and by chemically maintaining chromatin architecture in a closed state. DNA methylation can lead to gene silencing by either preventing or promoting the recruitment of regulatory proteins to DNA. For example, methylation can inhibit transcriptional activation by blocking transcription factors from accessing target-binding

DNA Hypermethylation in Cancer

Cancer initiation and progression are accompanied by profound changes in DNA methylation, the first epigenetic alterations identified in cancer [15]. A cancer epigenome is marked by site-specific CpG island promoter hypermethylation and genome-wide hypomethylation [16]. While the underlying mechanisms that initiate these global changes are still under investigation, recent studies indicate that some changes occur very early in cancer development and may contribute to cancer initiation [17].

DNA Hypomethylation in Cancer

The cancer genome is frequently characterized by an overall decrease in the level of 5-methyl cytosine, concurrent with the hypermethylation of specific genes. Originally, only DNA hypomethylation was linked with cancer and was the focus of tumor research [15], [55], [56]. Hypomethylation of the genome largely affects the intergenic and intronic regions of the DNA, particularly repeat sequences and transposable elements. It has been suggested to result in chromosomal instability and increased

Cancer Therapy and DNA Methylation

The response of cancers to different therapeutic agents can depend on the methylation status of a specific set of genes which, therefore, can be used as biomarkers to determine the clinical response to chemotherapy. For at least five genes, MGMT, MLH1, CPYP1B1, CPYP1A1, and DPYD, it was established that the extent in which these genes were methylated related to tumor progression [92], [93], [94], [95], [96], [97].

The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) counteracts

DNA Methylation Analysis

Over the past decade, a large number of techniques have been developed to analyze DNA methylation. Many of these techniques have had significant impact on epigenetic studies and on the development of methylation-based cancer diagnostics. Technologies for analysis of DNA methylation are based primarily on either PCR and sequencing after bisulfite conversion of unmethylated cytosines to uracil, or methylation-sensitive restriction enzymes. Identification of DNA methylation sites with

General Overview and Future Perspective

Advances made in the field of cancer epigenetics based on DNA methylation have led to the realization that the packaging of the genome is potentially as important as the genome itself in regulating the essential cellular processes required for preserving cellular identity and also in giving rise to disease states like cancer. Deeper understanding of the global patterns of these epigenetic modifications based on DNA methylation and their corresponding changes in cancer have enabled the design of

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