Uncoordinated expression of DNA methylation-related enzymes in human cancer

In addition to the important roles played by 5-methylcytosine (5mC), emerging evidence suggests that 5mC derivatives, such as 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), also exhibit regulatory functions in physiological and pathological processes. Four cytosine modifications (5mC, 5hmC, 5fC and 5caC) are produced and erased by a cyclic enzymatic cascade mediated by DNA methyltransferases (DNMTs), ten-eleven translocation (TET) family enzymes and thymine DNA glycosylase (TDG). Stable maintenance of the DNA methylation profile is important for normal cell homeostasis, but its underlying mechanisms are largely unknown.

The expression levels of 7 DNA methylation-related enzymes from normal mouse tissues were assessed using quantitative real-time RT-PCR (qRT-PCR). The gene expression data and related information of human normal tissues and tumor tissues were obtained from the Genotype-Tissue Expression (GTEx) and the Cancer Genome Atlas (TCGA), respectively.

We observed significant positive correlations among the expression levels of DNA methylation-related enzymes in various mice and human normal tissues. By contrast, we found significantly decreased correlations in various tumor tissues compared with their corresponding normal tissues. Furthermore, we also found that alterations in these correlations are associated with several clinicopathological characteristics of cancer patients.

These observations suggest that uncoordinated expression of DNA methylation-related enzymes is another epigenetic hallmark of cancer. Our work provides important insights into an additional regulatory layer of the DNA methylation maintenance machinery.