The role of vitamin C in epigenetic regulation

Vitamin C (L-ascorbic acid) is a micronutrient best known for its anti-scurvy activity in humans. Vitamin C is involved in many biological processes involving enzymatic reactions that are catalyzed by members of dioxygenases which use Fe(II) and 2-oxoglutarate as a co-substrate.The article reviews recent data that suggest the involvement of ascorbate in dioxygenases catalyzed chromatin and DNA modifications which thereby contribute to epigenetic regulation. Concerning chromatin modification, the dioxygenases are involved in distinct demethylation reactions with varying specificity for the position of the lysine on the target histone. TET hydroxylases catalyse the oxidation of methyl groups in the 5 position of cytosine in DNA yielding 5-hydroxymethylcytosine, while further iterative oxidation reactions results in the formation of 5-formylcytosine and 5-carboxylcytosine. A few previous studies demonstrated that ascorbate may enhance generation of 5-hydroxymethylcytosine in cultured cells, probably acting as a cofactor of TETs during hydroxylation of 5-methylcytosine. Physiological concentrations of ascorbate in human serum (10-100 μM) may guarantee stable level of 5-hydroxymethylcytosine, a modification necessary for epigenetic function of the cell. 5-Hydroxymethylcytosine level is substantially decreased in almost all investigated cancers, what may be linked with cancer development. Therefore, it is possible that supplementation with ascorbate could contribute to better management of individual cancer patient. This issue is also discussed in our paper.