Aberrant DNA methylation as a key modulator of cell death pathways: insights into cancer progression and other diseases.

Cell death plays a significant role in the physiology of all living organisms, and its disruption is the underlying cause of various diseases. Previously, it was assumed that apoptosis and necrosis were the only means of cell death. Recent discoveries of alternative cell death pathways highlighted a complicated interplay between cell death regulation and its role in numerous human pathologies. DNA methylation is a universal epigenetic mechanism characterized by the covalent addition of a methyl group to cytosine in CpG dinucleotides. Alterations in DNA methylation patterns lead to the dysregulation of multiple cell death pathways. DNA methylome studies on cell death pathways have improved our understanding of the mechanism of various types of cell death, such as apoptosis, pyroptosis, necroptosis, ferroptosis, anoikis, autophagy, and cuproptosis. The irregular DNA methylation patterns of genes encoding proteins linked to multiple cell death pathways could underlie resistance to cell death. Dysregulation of cell death is linked to ailments in humans, such as cancer. However, unlike genetic alterations, DNA methylation is reversible, making it extremely interesting for therapeutics considering the potential use of DNA methyltransferase inhibitors. Furthermore, tumor microenvironment and genetic heterogeneity of cancers may influence the methylation-dependent regulation of cell death, contributing to tumor progression and therapeutic resistance. Understanding how DNA methylation influences cell death pathways may illuminate the underlying causes of cancer. This review explores the significance of the DNA methylation patterns of key genes involved in cell death pathways, emphasizing their connections and identifying potential gaps that could be exploited for developing epigenetic therapies targeting cancer.