The role of 5-hydroxymethylcytosine in human cancer

Abstract

The patterns of DNA methylation in human cancer cells are highly abnormal and often involve the acquisition of DNA hypermethylation at hundreds or thousands of CpG islands that are usually unmethylated in normal tissues. The recent discovery of 5-hydroxymethylcytosine (5hmC) as an enzymatic oxidation product of 5-methylcytosine (5mC) has led to models and experimental data in which the hypermethylation and 5mC oxidation pathways seem to be connected. Key discoveries in this setting include the findings that several genes coding for proteins involved in the 5mC oxidation reaction are mutated in human tumors, and that a broad loss of 5hmC occurs across many types of cancer. In this review, we will summarize current knowledge and discuss models of the potential roles of 5hmC in human cancer biology.

Figure 1. Stability and propagation of DNA methylation patterns

A balance between DNA methylation and demethylation determines steady state levels of methylation at CpG sites.

Figure 2. Oxidation of 5-methylcytosine in a DNA demethylation pathway

Enzymes and reaction intermediates are shown schematically.

Figure 3. Reduced staining of 5-hydroxymethylcytosine in a melanoma biopsy

Different sections of the same biopsy showing an area of normal skin (A), normal skin adjacent to a melanoma (B; tumor in lower right quadrant) and a melanoma tumor section (C) were stained with anti-5hmC antibody and AP-blue dye (Blue Alkaline Phosphatase Substrate Kit, Vector Laboratories).