Navigating the DNA methylation landscape of cancer

• Published in: Trends in genetics Vol. 37; no. 11; pp. 1012 - 1027
• Main Authors: Nishiyama, Atsuya, Nakanishi, Makoto
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2021
• Subjects: cancer; CpG Islands - genetics; DNA methylation; DNA Methylation - genetics; DNA methyltransferase; Genome-Wide Association Study; histone modification; Humans; Neoplasms - genetics; Neoplasms - metabolism; DNA methylation; DNA methyltransferase; cancer; histone modification
• ISSN: 0168-9525
• DOI: 10.1016/j.tig.2021.05.002

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 methylation is an important epigenetic modification that defines the properties of cells. Genome-wide hypomethylation, as well as hypermethylation of CpG islands associated with tumor suppressor genes and developmental regulators, are characteristics of cancer cells.DNA methyltransferases normally exist in an inactive form and their localization and activation are regulated by interaction with unique histone modifications at DNA methylation sites.Changes in DNA methylation patterns associated with carcinogenesis progress gradually with cell proliferation. Genome-wide hypomethylation is found in DNA blocks called partially methylated domains (PMDs) and it frequently occurs in solo-WCGW sequences that have no nearby CpG sequences and are adjacent to A or C.CpG island methylation primarily targets promoters characterized by low gene expression marked by H3K27m3, with the replacement of histone modifications by DNA methylation ensuring more stable gene repression.