ROS-Mediated DNA Methylation Pattern Alterations in Carcinogenesis

Abstract

Elevated levels of both reactive oxygen species (ROS) and DNA methylation are characteristic of various types of cancer cells. However, the relation between these two is not well understood. Here we will discuss the cause-consequence relationship between ROS and DNA methylation. Cancer research reveals that disregulation of DNA methylation results in regional CpG island hypermethylation and generalized genomic hypomethylation. ROS-induced oxidative stress is associated with both aberrant hypermethylation of tumor suppressor gene (TSG) promoter regions and global hypomethylation. The DNA oxidation structure, 8-hydroxy-2'-deoxyguanosine (8-OHdG), can induce DNA hypomethylation by inhibiting DNA methylation at nearby cytosine bases, while another DNA oxidation structure, 5-hydroxymethylcytosine (5hmC), may achieve active DNA demethylation processes, thus, causing DNA hypomethylation. Recently, it has been found that ROS can function as catalysts of DNA methylation, further accounting for TSG promoter hypermethylation. Moreover, ROS may induce site-specific hypermethylation via either the up-regulation of expression of DNA methyltransferases (DNMTs) or the formation of a new DNMT containing complex. In addition, these ROS-induced DNA methylation pattern alterations have been implicated with not only malignant transformation, but also the progression of numerous tumors. In conclusion, ROS can influence both aspects of DNA methylation changes through different mechanisms, which play an important role of epigenetic regulation in cancer cells. Therefore, the comprehension of mechanisms leading to epigenetic modifications associated with ROS may help better understand the carcinogenesis and progression, as well as aid in the development of potential biomarkers for better cancer diagnostics and novel therapeutic strategies.

The effect of morphine upon DNA methylation in ten regions of the rat brain

“…49 Elevated ROS levels are known to induce site-specific alterations in DNA methylation by mechanisms such as modulation of the expression of DNA methyltransferases (DNMTs). 50 While the observed gene-specific changes in DNA methylation are likely to be directly induced by morphine administration, global changes in 5-mc and 5-hmc content could in part be non-specific effects through increased ROS production.…”

Biological chemistry and functionality of protein sulfenic acids and related thiol modifications

“…Changes in the cellular redox status are implicated in the regulation of epigenetic processes contributing to the development and progression of cancer [221–223]. One such epigenetic modification is DNA methylation, which is tightly regulated by the action of DNA methyltransferases enzymes such as DNMT1, DNMT3A and DNMT3B [224].…”

DNA hypermethylation-mediated downregulation of antioxidant genes contributes to the early onset of cataracts in highly myopic eyes

“…Previously, there have also been studies proving the role of DNMT1 in addressing the possible influence of elevated oxidative stress on genome-wide DNA methylation levels [40]. Wu et al reported that reactive oxygen species might induce site-specific hypermethylation via either the overexpression of DNMTs or the formation of a new DNMT-containing complex that better catalyzes this modification [41]. Our study discovered that, compared to LECs from ARC cases, LECs from HMC cases showed higher expression of DNMT1 at both the mRNA and protein levels, where the LECs were in a condition with higher levels of oxidative stress.…”