Mini-reviewOxidative stress, DNA methylation and carcinogenesis
Introduction
Oxidative stress has long been known to be involved in the pathophysiology of many human diseases including, but not restricted, to cancer. The term “oxidative stress”, refers to a cell’s state characterized by excessive production of reactive oxygen species (ROS) and/or a reduction in antioxidant defenses responsible for their metabolism. This generates an imbalance between ROS production and removal in favor of the former.
Cancer is a multistage process and often involves “alterations” or “changes” in the transcriptional activity of genes associated with many critical cellular processes for tumor development including proliferation, senescence, inflammation, metastasis, etc. Furthermore, there are known to be both genotoxic and non genotoxic mechanisms contributing to malignant transformation. Generally, genotoxic mechanisms involve changes in genomic DNA sequences that ultimately lead to mutations whereas non-genotoxic include mechanisms (other than directly affecting DNA) capable of modulating gene expression. ROS have been implicated at all stages of the carcinogenic process by involving both types of mechanisms [1].
On the other hand, the term “epigenetics” refers to altered levels of a gene’s transcriptional activity without directly affecting its primary DNA nucleotide sequence. It involves alterations in DNA methylation patterns that together with specific histone modifications (methylations, acetylations, deacetylations, etc.) contribute to a transcriptional inactive chromatin state [2]. In this respect, epigenetic regulation of gene expression can be viewed as a non genotoxic mechanism for promoting tumor formation.
Throughout this review article, we will present the evidence for the involvement of oxidative stress in carcinogenesis, consider the evidence for its role in inducing DNA methylation changes and assess the importance of these changes in the multistage process of human carcinogenesis.
Section snippets
Sources of ROS
There are both endogenous and exogenous sources of ROS generation. Endogenous sources include those of: (1) mitochondrial oxidative phosphorylation, (2) P450 metabolism, (3) peroxisomes and (4) activation of inflammatory cells. It has been postulated that during oxidative phosphorylation 1–2% of molecular oxygen is converted to ROS primarily through a series of sequential one-, two- and three-electron reductions giving rise to superoxide, hydrogen peroxide and hydroxyl radical formation
Involvement of oxidative stress in carcinogenesis
In general, the multistage process of carcinogenesis involves the distinct phases of initiation, promotion and progression. The cellular and molecular events underlying each of these phases include DNA damage, increased proliferation, deficient cell death and further genetic instability, respectively [1], [4].
Oxidative DNA damage can trigger tumor initiation. More specifically, studies using ionizing radiation have shown multiple hydroxyl radical-induced genotoxic by- products in the bases as
The role of epigenetics in carcinogenesis
In general, increased DNA methylation in the promoter region of genes causes gene silencing and in this respect can contribute to the multistage process of carcinogenesis. In addition, in mammalian cells, both DNA methylation and chromatin structure are interconnected in specific ways so that genes will either be transcribed or repressed. Briefly, the process is initiated by DNA methyltransferases (DNMTs) bringing together the DNA methylation machinery to the chromatin through recruitment of
Involvement of oxidative stress in DNA methylation
Oxidative stress can contribute to tumor development not only through genetic but also through epigenetic mechanisms. As it was mentioned earlier on, generation of the hydroxyl radical can cause a wide range of DNA lesions including base modifications, deletions, strand breakage, chromosomal rearrangements, etc. Such DNA lesions have been shown to interfere with the ability of DNA to function as a substrate for the DNMTs, resulting in global hypomethylation [34]. More specifically, X-rays [35],
Conclusions and perspectives
It is evident that ROS-induced oxidative stress is involved in the multistage process of carcinogenesis by both genetic and epigenetic mechanisms. In particular, there seems to be a growing interest (by many investigators) in the involvement of oxidative stress in the epigenetic regulation of gene expression and specifically in controlling DNA methylation. Given the recent findings in detecting circulating tumor DNA in patients with cancer [55], it becomes of paramount importance to reveal the
Acknowledgements
This work was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH)/National Institute of Environmental Health Sciences (NIEHS) (Onard Schoneveld and Rodrigo Franco).
Dr. Georgakilas has been supported by funds provided by the Biology Department of East Carolina University and a College Research Award (East Carolina University). Finally, Dr. Panayiotidis has been supported by funds provided by the School of Public Health of the University of Nevada at
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Both authors have contributed equally to the preparation of the manuscript.