DNA hypomethylation in cancer cells

Abstract

DNA hypomethylation was the initial epigenetic abnormality recognized in human tumors. However, for several decades after its independent discovery by two laboratories in 1983, it was often ignored as an unwelcome complication, with almost all of the attention on the hypermethylation of promoters of genes that are silenced in cancers (e.g., tumor-suppressor genes). Because it was subsequently shown that global hypomethylation of DNA in cancer was most closely associated with repeated DNA elements, cancer linked-DNA hypomethylation continued to receive rather little attention. DNA hypomethylation in cancer can no longer be considered an oddity, because recent high-resolution genome-wide studies confirm that DNA hypomethylation is the almost constant companion to hypermethylation of the genome in cancer, just usually (but not always) in different sequences. Methylation changes at individual CpG dyads in cancer can have a high degree of dependence not only on the regional context, but also on neighboring sites. DNA demethylation during carcinogenesis may involve hemimethylated dyads as intermediates, followed by spreading of the loss of methylation on both strands. In this review, active demethylation of DNA and the relationship of cancer-associated DNA hypomethylation to cancer stem cells are discussed. Evidence is accumulating for the biological significance and clinical relevance of DNA hypomethylation in cancer, and for cancer-linked demethylation and de novo methylation being highly dynamic processes.

Keywords: DNA methylation; DNA repeats; cancer; genomic sequencing; hypermethylation; hypomethylation.

Conflict of interest statement

Financial & competing interests disclosure: The author is supported in part by grant R01 NS048859 from the National Institutes of Health and a grant from the Louisiana Cancer Research Consortium. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1. Similarilities and differences in cancer-associated hypo- and hyper-methylation of DNA

Figure 2. A comparison of active and passive pathways for DNA demethylation and, in particular, for generating neighboring hemimethylated CpG dyads with opposite polarity

This figure demonstrates that it is unlikely that inhibition of passive demethylation is responsible for producing such DNA methylation patterns, which were observed in both cancers and normal tissues. Although neighboring, oppositely-oriented hemimethylated dyads (pink highlighting) were seen only infrequently, they were found in three different hairpin sequencing studies of DNA methylation and in normal tissues as well as cancer samples [–106]. We conclude that active demethylation is responsible for at least some of the demethylation in vivo.