Reactive oxygen species (ROS) stress plays an important role in the progression of various tumors. DNA methylation is the most frequent epigenetic alteration in mammalian genomes, frequently mediating transcriptional repression of tumor suppressor gen ...

Reactive oxygen species (ROS) stress plays an important role in the progression of various tumors. DNA methylation is the most frequent epigenetic alteration in mammalian genomes, frequently mediating transcriptional repression of tumor suppressor genes in cancer cells. ROS stress and loss-of-function of tumor suppressor genes by promoter hypermethylation contribute to tumor cell invasion and metastasis. However, it remains unclear whether or how ROS trigger epigenetic changes in cancer cells. Here we demonstrate that ROS induce hypermethylation of the E-cadherin promoter through increased Snail expression. We found that Snail induces DNA methylation of the E-cadherin promoter by recruiting histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1). In human hepatocellular carcinoma (HCC) tissues, we also observed a positive correlation among ROS stress, E-cadherin down-regulation, Snail up-regulation, and E-cadherin promoter methylation. Our data provide novel mechanistic insights into epigenetic modulations induced by ROS stress in the process of carcinogenesis. This finding is potentially relevant to the activity of ROS in silencing various tumor suppressor genes, a frequent occurrence in highly metastatic cancers.

In this report, we analyzed promoter regulation via Snail and methylation and identified a link between these two factors. In HCC cells, ROS induced the up-regulation of Snail expression and the methylation of the E-cadherin promoter. Specifically, Sn ...

In this report, we analyzed promoter regulation via Snail and methylation and identified a link between these two factors. In HCC cells, ROS induced the up-regulation of Snail expression and the methylation of the E-cadherin promoter. Specifically, Snail induced methylation of CpG sites in the E-cadherin promoter. We also investigated alterations by ROS in Snail expression and E-cadherin promoter methylation in human HCC tissue specimens. Overall, we showed that ROS induced methylation of the E-cadherin promoter via Snail.
In conclusion, we identify a new role of ROS ？ to trigger DNA methylation of tumor suppressor gene promoters in carcinogenesis. We suggest a functional pathway model of ROS-inducing epigenetic changes in which persistently elevated ROS induces CpG methylation in the E-cadherin promoter via specific recognition of an E-box by Snail. Together with human tissue data, our suggested model provides direct evidence that persistently high levels of ROS stress trigger epigenetic changes in cancer cells. This mechanism is also potentially relevant to the role of ROS in hypermethylating various tumor suppressor genes. Understanding these roles of ROS could lead to epigenetic therapy for cancer using HDAC and DNMT inhibitors in combination with various antioxidants.