Dr. Wang's research focuses on understanding the role of vitamin C (ascorbate), as a cofactor for DNA demethylases and histone demethylases, in cancer initiation and progression. The primary goal of his research is to determine whether vitamin C treatment can restore, at least partially, the epigenetic profiles and ultimately lead to an epigenetic reprogramming of cancer cells toward healthy cells. The long-term goal is to develop nutritional supplements for cancer prevention and to identify novel druggable targets for cancer treatment.
One recent breakthrough in the epigenetics field is the identification of DNA demethylation pathways. A group of enzymes termed ten-eleven translocation (TET) dioxygenases were discovered to catalyze the hydroxylation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which cannot be recognized by DNA methyl-transferases (DNMT), leading to replication-dependent demethylation. TET can further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which are eventually replaced by unmodified cytosine, thus completing the process of replication-independent active DNA demethylation.
Dr. Wang and colleagues are the first to publish that vitamin C is a cofactor for TET enzymes, as it does for other iron and 2-oxoglutarate dependent hydroxylases. Their findings were confirmed by later reports from other groups and are now widely accepted. Compelling evidence has shown that loss of 5hmC is found in most, if not all, types of human cancer. Interestingly, the expression of vitamin C transporters is also decreased in many types of cancers. It is plausible that 5hmC deficit in cancer could be caused, at least partly, by a local deficiency of vitamin C, which must be addressed in clinical care of cancer patients. Furthermore, vitamin C has been shown as a cofactor for a few of, but potentially could be many, histone demethylases, most of which also are iron and 2-oxoglutarate dependent dioxygenases. Dr. Wang's research is dissecting the role of vitamin C in histone demethylation in cancer development.
Continuing the DNA demethylation research, his lab has made a breakthrough progress. In a recent publication in eLIFE, they showed that G-protein coupled receptors (GPCRs), via cAMP, regulate DNA demethylation and the transcriptome by modulating the intracellular labile Fe(II) pool. Thus, GPCRs can transduce environmental cues such as pharmaceutical drugs, various hormones, and neurotransmitters into the second messenger cAMP and further to alterations in DNA methylation, which could be implicated in human health and disease. There are about 800 GPCRs in humans and nearly 50% of all marketed drugs target GPCRs. More importantly, GPCRs play critical roles in cancer and GPCRs have been recognized as emerging anti-cancer drug targets. Thus, his research is also working on the epigenetic role of GPCRs in cancer treatment.