Navigating the DNA methylation landscape of cancer

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. DNA methylationDNA methylation is a chemical modification that plays an important role in the regulation of epigenetic gene expression [1-3], genomic imprinting [4-6], X chromosome inactivation [7,8], transposon (see Glossary) silencing [9], and genome stability [10,11]. DNA methylation is mainly catalyzed by three enzymes, DNMT1, DNMT3A, and DNMT3B (Figure 1). 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. DNMT1 inactivation and DNMT3A/3B double knockout (KO) mouse embryos show significant growth inhibition and are lethal before mid-gestation [12,13]. In contrast, DNA methylation is not necessarily required in embryonic stem (ES) cells; even when CpG methylation is completely lost by combined KO of three DNMTs Dnmt1, Dnmt3a, and Dnmt3b, there is a minimal change in phenotype in undifferentiated ES cells [14]. Although DNA methylation is a stable modification, there are also several pathways of demethylation and these pathways play an important role in the regulation of DNA methylation in various biological contexts (Box 3). In normal cells, 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. In addition, systematic analysis of unmethylated DNA and methylated CpG as ligands has revealed that DNA methylation promotes the binding of many transcription factors [17]. Recently, broad unmethylated regions were also reported as DNA methylation canyons [18] or DNA methylation valleys [19] that are associated with either the active histone mark H3K4me3 or the inhibitory mark H3K27me3.Accumulating evidence demonstrate that cancer cells show largely di...

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“…Cancer cells are characterized by aberrant DNA methylation (e.g., genome-wide hypomethylation and site-speci c hypermethylation), mainly targeting CpG islands in gene expression regulatory elements. In particular, the early ndings that a variety of tumor suppressor genes 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 (Nishiyama and Nakanishi, 2021). The present study showed that DNA methylation of GDF15 was downregulated in most common cancers, which is consistent with the upregulation of the GDF15 expression.…”

Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

“…In mammals, three active DNMTs are found and designated as DNMT1, DNMT3a, and DNMT3b. As there are many excellent reviews on these enzymes and DNA methylation, we refer our readers to a few of these comprehensive articles [ 23 – 25 ].…”

Epigenetic Priming with Decitabine Augments the Therapeutic Effect of Cisplatin on Triple-Negative Breast Cancer Cells through Induction of Proapoptotic Factor NOXA

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