DNA Methylation: Its Role in Cancer Development and Therapy

Abstract

Inflammation and Methylation ChangesChanges in the genome which result in cancer promotion remain a complex interplay of aberrant methylation in the setting of a multitude of epigenetic changes. The events leading to these disruptions in methylation have been postulated; though remain to be fully elucidated. A causal relationship between inflammation and cancer has long been accepted in multiple tumor types, most prominently colon cancer; an association supported by the evidence that non-steroidal anti-inflammatory medications can potentially stop the development of colon cancer. Investigations in patients with ulcerative colitis who have a predisposition to the development of colon cancer have established a potential link between inflammation and cancer by the demonstration of hypermethylated gene promoters in early dysplastic lesions. 1 The mechanisms responsible for the contribution of inflammation to cancer remain to be fully understood. Mutagenesis resulting from the production of halogenated nucleotide precursors in activated neutrophils and eosinophils with subsequent incorporation into DNA has been demonstrated in vitro. 2,3 The link between inflammation-induced halogenated nucleotides and aberrant methylation stems from the demonstration that methyl-binding proteins cannot distinguish between methylated cytosine residues and chlorinated or brominated cytosine nucleotides. Furthermore, DNMT1 also could not distinguish between 5-methylcytosine and some 5-halocytosine products which could potentially result in mistaken methylation at sites of inflammation. 4 These halogenated cytosine residues were not recognized by DNA repair enzymes suggesting the possibility of accumulation of heritable changes within the genome.Infection with Helicobacter pylori has been implicated in the development of gastric cancer with a relative risk increase of 2.2-to 6 fold when infection is detected. 5-8 The mechanism of cancer development in this setting has been attributed to inflammation leading to cell proliferation resulting in a propensity for gene mutation. Aberrant methylation due to H. pylori infection has been suggested as an additional mechanism bridging the gap between inflammation and cancer. In a series of 154 healthy volunteers and 72 patients with gastric cancer, methylation of 8 regions of 7 CpG islands was assessed. 14 Among the healthy volunteers, the extent of DNA methylation was 5.4-to 303-times higher in the H. pylori positive cases compared to the H. pylori negative cases (p<0.0001) suggesting an increase in methylation levels due to the presence of H. pylori. However, the comparison of methylation levels between healthy volunteers and patients with gastric cancer stratified by H. pylori status

Prognostic and Predictive Value of Cell Cycle Deregulation in Non-Small-Cell Lung Cancer

“…Thus, patients with tumors harboring epigenetic alterations could benefit from treatment with demethylating agents. 5-Azacytidine is a demethylating agent that inhibits DNA methyltransferase 1 in replicating cells [100] and has recently been shown to prolong survival and improve quality of life in patients with myelodysplastic syndromes, while maintaining a favorable adverse-effect profile [101]. Prospective studies in NSCLC with promising results are ongoing [102].…”

DNMT3A −448A>G polymorphism and the risk for hepatocellular carcinoma

“…Aberrant changes of genomic methylation patterns or abnormal interpretation of the DNA methylation signals are associated with several human disorders, most notably immunodeficiency, centromeric instability, facial anomalies syndrome, Rett syndrome and cancer (14). The expression of these DNMTs is significantly elevated in various types of cancer including breast, colon, endometrium, prostate, stomach and in uterine leiomyomata (15). In a previous study, DNMT3A expression was increased in 3/6 HCC cell lines and 16/25 (64%) HCC tissues, suggesting that DNMT3A is involved in hepatocellular carcinogenesis (16).…”

Regulation of estrogen receptor beta activity and implications in health and disease

“…In most of the studies, the findings were complemented with 5-AZAC treatment of cell lines, which led to demethylation of the promoter and subsequent ERb re-expression. DNA demethylation agents, alone or in combination with histone deacetylase (HDAC) inhibitors, are used in cancer therapy, for example for myelodysplastic syndromes, leukemia, and ovarian and prostate cancer (reviewed in, e.g., [198]). In vitro studies also demonstrate that DNA demethylation agents, particularly in combination with HDAC inhibitors, induce apoptosis, cell differentiation and/or growth arrest, e.g., in human lung, breast, colon, and prostate cancer cells [199,200].…”