Abstract
Cancer initiation and progression toward malignant stages occur as the results of accumulating genetic alterations and epigenetic dysregulation. During the last decade, the development of next generation sequencing (NGS) technologies and the increasing pan-genomic knowledge have revolutionized how we consider the evolving epigenetic landscapes during homeostasis and tumor progression. DNA methylation represents the best studied mark and is considered as a common mechanism of epigenetic regulation in normal homeostasis and cancer. A remarkable amount of work has recently started clarifying the central role played by DNA methylation dynamics on the maintenance of cell identity and on cell fate decisions during the different steps of normal development and tumor evolution. Importantly, a growing number of studies show that DNA methylation is key in the maintenance of adult stemness and in orchestrating commitment in multiple ways. Perturbations of the normal DNA methylation patterns impair the homeostatic balance and can lead to tumor initiation. Therefore, DNA methylation represents an interesting therapeutic target to recover homeostasis in tumor stem cells.
Highlights
According to its most popular definition, epigenetics describes the acquisition of measurable and stably heritable phenotypic traits that do not depend on changes in the DNA sequence itself [1].Epigenetic control, mediated by the integrative network of histone and DNA covalent modifications, as well as noncoding RNAs, coordinates the cell phenotype and allows genetically identical cells to achieve diverse phenotypic characteristics by modulating the accessibility of different regions of the genome through differential packaging and decoration of the chromatin
This review aims at summarizing and discussing the most relevant knowledge on the role of DNA methylation in normal homeostasis and its implications in cancer initiation, by focusing on the control exerted by this epigenetic mark on the dynamics of adult stem/progenitor populations in both these processes
Methylation in homeostasis and cancer, which highlighted a significant contribution of epigenetic control to the transition between the two states
Summary
According to its most popular definition, epigenetics describes the acquisition of measurable and stably heritable phenotypic traits that do not depend on changes in the DNA sequence itself [1]. Stochastic, environmentally-induced epigenetic imbalance of stem cells would be followed by a cancer initiating hit involving tumor suppressors or oncogenes in the population of epigenetically disrupted progenitors This genetic alteration further increases the genetic and epigenetic plasticity of the progeny, allowing the subsequent development of distinct subclones responsible for tumor evolution. Some epigenetic features appear almost universal in human advanced neoplasia and are considered to represent hallmarks of cancer, which has led to the general assumption that those alterations occur very early during tumor development These alterations include the hypomethylation of the genome in cancer cells, which can be accompanied by the focal hypermethylation of tumor suppressor genes. Oncogenic alterations induce ofControl focal ofalteration of DNA methylation impairAthe
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