DNA methylation in cancer development, diagnosis and therapy--multiple opportunities for genotoxic agents to act as methylome disruptors or remediators

Abstract

The role of DNA methylation and recently discovered hydroxymethylation in the function of the human epigenome is currently one of the hottest topics in the life sciences. Progress in this field of research has been further accelerated by the discovery that alterations in the methylome are not only associated with key functions of cells and organisms, such as development, differentiation and gene expression, but may underlie a number of human diseases, including cancer. This review describes both well established and more recent observations concerning alterations in the methylome, i.e. the global and local distribution of 5-methylcytosines, involved in its normal functions. Then, the changes in DNA methylation pattern seen in cancer cells are discussed in the context of their utilisation in cancer diagnostics and treatment. On this basis, comparisons are made between natural covalent DNA modification and that induced by genotoxic agents, chemical carcinogens and antitumour drugs as regards their impact on epigenetic mechanisms. The available data suggest that DNA damage by genotoxins can mimic epigenetic markers and in consequence disrupt the proper function of the epigenome. On the other hand, the same processes in cancer cells, e.g. DNA demethylation as a result of DNA methyltransferase blocking or the induction of DNA repair by DNA adducts, may restore the activity of hypermethylated anticancer genes. The observed multiple mechanisms by which genotoxic agents directly affect methylome function suggest that chemical carcinogens act primarily as epigenome disruptors, whereas mutations are secondary events that occur at later stages of cancer development when genome-protecting mechanisms have already been deregulated.

Myeloma Is Characterized by Stage-Specific Alterations in DNA Methylation That Occur Early during Myelomagenesis

“…Although we cannot show a clear reason for this, others have shown that exposure to chemotherapy can lead to large scale genetic and epigenetic changes in tumor samples (reviewed in (32–34)). The relapsed cases examined in our cohort were heavily pretreated patients who have been exposed multiple MM agents including Bortezomib.…”

Regulation of AURKC expression by CpG island methylation in human cancer cells

“…Aberrant DNA methylation has been a hallmark of several cancers leading to genomic instability [35]. Hyper-and hypo-methylation of tumor suppressor genes, hormone-responsive elements, cell adhesion, and microRNA encoding genes have been well documented in cancers [36]. Cell cycle regulators are another class of genes which, when aberrantly methylated, may lead to genomic instability and carcinogenesis.…”

Antioxidants: A Premature Scientific Hypothesis that Reshuffled the Traditional Food Pyramid

“…Currently, however, it is considered as an element of redox sensitive epigenetic regulation (Guz et al 2012). The dual role of genotoxins-including agents known to induce DNA oxidation-as possible methylome disruptors and remediators has been suggested as well (Lewandowska and Bartoszek 2011). An altered pattern of DNA methylation is observed in many diseases, especially in cancer and neurological disorders, which are prevented by dietary antioxidants.…”