Abstract
BackgroundAberrant DNA methylation plays important roles in carcinogenesis. However, the functional significance of genome-wide hypermethylation and hypomethylation of gene promoters in carcinogenesis currently remain unclear.Principal FindingsBased on genome-wide methylation data for five cancer types, we showed that genes with promoter hypermethylation were highly consistent in function across different cancer types, and so were genes with promoter hypomethylation. Functions related to “developmental processes” and “regulation of biology processes” were significantly enriched with hypermethylated genes but were depleted of hypomethylated genes. In contrast, functions related to “cell killing” and “response to stimulus”, including immune and inflammatory response, were associated with an enrichment of hypomethylated genes and depletion of hypermethylated genes. We also observed that some families of cytokines secreted by immune cells, such as IL10 family cytokines and chemokines, tended to be hypomethylated in various cancer types. These results provide new hints for understanding the distinct functional roles of genome-wide hypermethylation and hypomethylation of gene promoters in carcinogenesis.ConclusionsGenes with promoter hypermethylation and hypomethylation are highly consistent in function across different cancer types, respectively, but these two groups of genes tend to be enriched in different functions associated with cancer. Especially, we speculate that hypomethylation of gene promoters may play roles in inducing immunity and inflammation disorders in precancerous conditions, which may provide hints for improving epigenetic therapy and immunotherapy of cancer.
Highlights
DNA hypermethylation and hypomethylation play important roles in the initiation, progression and metastasis of cancer [1,2]
Genes with promoter hypermethylation and hypomethylation are highly consistent in function across different cancer types, respectively, but these two groups of genes tend to be enriched in different functions associated with cancer
DNA hypermethylation in cancer genomes usually occurs in the promoter regions of tumor suppressor genes, which can result in silencing of tumor suppressor genes [5]
Summary
DNA hypermethylation and hypomethylation play important roles in the initiation, progression and metastasis of cancer [1,2]. There is evidence that promoter hypomethylation of some genes may be associated with the development of cancer by regulating the activity of genes [10] and that promoter hypomethylation of specific immunity-related genes may promote carcinogenesis [11,12]. The promoter hypomethylation of cytokine IL-10 can activate its expression to inhibit the generation of immune response in breast cancer [11], and the promoter hypomethylation of SPAN-Xb, an immunogenic antigen, can induce de novo B-cell response in myeloma cells [12]. The functional significance of genome-wide hypermethylation and hypomethylation of gene promoters in carcinogenesis currently remain unclear
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