Chapter 7 - Methylation of DNA in Cancer
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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