Inflammation-Mediated Cytosine Damage: A Mechanistic Link between Inflammation and the Epigenetic Alterations in Human Cancers

Abstract

Aberrant methylation patterns have long been known to exist in the promoter regions of key regulatory genes in the DNA of tumor cells. However, the mechanisms by which these methylation patterns become altered during the transformation of normal cells to tumor cells have remained elusive. We have recently shown in in vitro studies that inflammation-mediated halogenated cytosine damage products can mimic 5-methylcytosine in directing enzymatic DNA methylation and in enhancing the binding of methyl-binding proteins whereas certain oxidative damage products inhibit both. We have therefore proposed that cytosine damage products could potentially interfere with normal epigenetic control by altering DNA-protein interactions critical for gene regulation and the heritable transmission of methylation patterns. These inflammation-mediated cytosine damage products may provide, in some cases, a mechanistic link between inflammation and cancer.

Chemical and cytokine features of innate immunity characterize serum and tissue profiles in inflammatory bowel disease

“…Although the average values in mouse colons were higher than those found in human tissues, the range of data were overlapping (Fig. 1), which suggests that 5-Cl-dC may be a contributing factor in the initiation of colon carcinogenesis through either mutational or gene silencing mechanisms (54)(55)(56).…”

Age-related loss of CpG methylation in the tumour necrosis factor promoter

“…Another potential mechanism is related to the effects of chronic age-related low grade inflammation leading to the production of reactive oxidative molecules with resultant conversion of 5-methylcytosine to 5-hydroxymethylcytosine [34]. This modification interfers with the activities of DNA methyltransferase 1 with failure to methylate target cytosines [34], however once again this mechanism would also be expected to result in a genomic rather than a gene specific change in methylation. The conversion of 5-methylcytosine to 5-hydroxymethylcytosine is regulated by members of the TET protein family [35], however little is known of the effects of ageing on TET.…”

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

“…Interestingly, one of the mechanisms that leads to microsatellite instability is inhibition of MLH1 expression, a key mismatch repair protein, by hypermethylation (59). As mentioned earlier, one biochemical feature of 5ClC, when present in CpG islands, is the ability to induce DNA hypermethylation (25,60). Therefore, we speculate that signature 6 (and/or signature H) may reflect both the mutagenic and the epigenetic features of genomic 5ClC accumulation and thus represent the mutational signature of neutrophil-driven chronic inflammation (Fig.…”