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 may become 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 there is a broad loss of 5hmC 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.

A Sensitive Approach to Map Genome-wide 5-Hydroxymethylcytosine and 5-Formylcytosine at Single-Base Resolution

“…In addition, we were able to achieve a genome-wide mapping for 5fC at single-base resolution. This highly sensitive method makes it possible to study both 5hmC and 5fC in precious samples, where a large amount of DNA is difficult to produce, or in cell types where the 5hmC modification abundance is low, such as cancer cells, in which 5hmC is scarce, yet may play important roles (Pfeifer et al, 2014). We noted a distinction in 5hmC as well as 5fC modifications between the CpG and CH contexts.…”

5-Hydroxymethylcytosine: A stable or transient DNA modification?

“…As we will discuss below, 5hmC is strongly associated with genes and regulatory elements in the genome, is abundant in brain, ES cells, primordial germ cells, and in fertilized oocytes. 5hmC is depleted in many types of human cancer [17], a topic that will not be discussed here in further detail but has been reviewed recently [18, 19] [ see also review by Ficz and colleagues, this issue]. The fact that 5hmC can be established by three different Tet enzymes, Tet1, Tet2 and Tet3, which are differentially expressed during development and tissue formation and target diverse genomic regions such as gene body, promoters or enhancers, suggests that 5hmC may play a multifaceted role in genome biology.…”

Epigenetics and Carcinogenesis: DNA Methylation Abnormalities Associated with Cancer and their Possible Source

“…One is by enzymatic demethylation, a process that is known to occur as a result of the oxidation of 5-methylcytosine to its hydroxylated derivative. This involves 'ten-eleven translocase' (TET) enzymes [14] and ultimately leads to base excision repair with replacement by unmethylated cytosine. Such a process is likely to constitute a random outcome of metabolic oxidation.…”