Abstract
DNA methylation is a chemical modification that defines cell type and lineage through the control of gene expression and genome stability. Disruption of DNA methylation control mechanisms causes a variety of diseases, including cancer. Cancer cells are characterized by aberrant DNA methylation (i.e., genome-wide hypomethylation and site-specific hypermethylation), mainly targeting CpG islands in gene expression regulatory elements. In particular, the early findings that a variety of tumor suppressor genes (TSGs) are targets of DNA hypermethylation in cancer led to the proposal of a model in which aberrant DNA methylation promotes cellular oncogenesis through TSGs silencing. However, recent genome-wide analyses have revealed that this classical model needs to be reconsidered. In this review, we will discuss the molecular mechanisms of DNA methylation abnormalities in cancer as well as their therapeutic potential.
Highlights
DNA methylation is a chemical modification that defines cell type and lineage through the control of gene expression and genome stability
Clinical applications of DNA methyltransferases (DNMTs) inhibitors targeting the transcriptional inactivation of tumor suppressor genes (TSGs) via DNA methylation, as well as tissue-specific DNA methylation profile, are currently underway
The overexpression of UHRF1 in hepatocellular carcinoma (HCC) cells correlates with the inactivation of p53 and changes in DNA copy number [110], suggesting that genomic instability associated with DNA hypomethylation and p53 inactivation are important for the oncogenic process
Summary
DNA methylation is a chemical modification that defines cell type and lineage through the control of gene expression and genome stability. Cancer cells are characterized by aberrant DNA methylation (i.e., genome-wide hypomethylation and site-specific hypermethylation), mainly targeting CpG islands in gene expression regulatory elements. Genome-wide hypomethylation, as well as hypermethylation of CpG islands associated with tumor suppressor genes and developmental regulators, are characteristics of cancer cells. De novo DNA methylation is mainly catalyzed by the DNA methyltransferases (DNMTs) DNMT3A and 3B (Box 1), while established DNA methylation patterns are maintained by the daughter DNA through a maintenance DNA methylation mechanism during cell proliferation (Box 2) Both de novo DNA methylation and maintenance DNA methylation are important for normal development. Most CpG sequences in the genome are methylated, but CpG islands and the nearby CpG island shores (the region within 2 kb of the islands) are exceptionally hypomethylated [15,16] Many of these hypomethylated regions of DNA function as elements that regulate gene expression, such as promoters and enhancers.
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