What Is DNA Methylation?

Epigenetics define the heritable regulation of gene expression that is not caused by changes in DNA sequences. Among the many types of epigenetic modifications, DNA methylation is probably the best-studied one. Most DNA methylation occurs in the context of CpG dinucleotides (where a cytosine is followed by a guanine). When located within gene promoter regions, methylated CpG dinucleotides often repress downstream gene expression, a common epigenetic regulation shared by vertebrates.

DNA methylation is essential during vertebrate development, as genes need to be turned on and off accordingly to ensure the proper progression of various biological processes. Alterations in DNA methylation pattern have frequently been observed in a range of diseases including cancer.

The Use of DNA Methylation Inhibitors for Cancer Treatment

Researchers have been actively looking into the connections between DNA methylation and cancer, hoping to target the DNA methylation pathway for cancer treatment. One of the DNA methylation inhibitors, 5-Azacytidine (Vidaza), was approved by the FDA for the treatment of blood cancers in 2004.

Vidaza works as a cytidine analog that can incorporate into the newly synthesized DNA. The analog forms an irreversible linkage between DNA methyltransferase enzymes, which triggers the enzyme degradation and eventually results in reduced overall levels of DNA methylation. It functions, at least in part, by de-repressing genes silenced in cancer cells, such as tumor-suppressor genes.

Although Vidaza significantly extends overall survival of patients with myelodysplastic syndromes compared with conventional regimens, the use of Vidaza is often associated with toxic side effects. Moreover, Vidaza itself is unstable and unavailable for oral administration.

Another type of cytidine analog, Zebularine, works similarly as Vidaza with comparable efficacy. However, Zebularine is more stable and can be orally taken. It is the first drug of its kind that does not require intravenous injection.

The Future of DNA Methylation Therapy

Beyond cytidine analogs, researchers are also investigating small molecules that can directly inhibit the function of DNA methyltransferase enzymes. One of such small molecules, called RG108, shows promising results as it significantly re-expresses tumor suppressor gene p16 in cancer cells. Importantly, because R108 does not intercalate into DNA or degrade DNA methyltransferase enzymes, it has relatively low toxicity. These drugs hold great promise as the second generation of methylation inhibiting drugs for cancer therapy.

DNA methylation inhibiting drugs have more success in treating blood cancers over solid tumors, partly due to the labile nature of cytidine analogs as well as the slower replicating rate of the tumor cells. Nevertheless, new studies have demonstrated the additional benefits of DNA methylation inhibiting drugs when combined with other types of cancer therapy.

New Prospects for Cancer Treatment

Immunotherapy has taken off in the past decade as scientists have figured out ways to utilize the human immune system to eliminate cancer cells. Vidaza treatment has been shown to improve the response of anti-CTLA4 immune checkpoint therapy in the mouse model of melanoma. The underlying mechanism is that DNA methylation inhibitors cause the expression of viral genes and trigger the immune response, which sensitizes cancer cells to immunotherapy. It will be of great interest to investigate whether the same principle holds true in humans and other types of solid tumors.

Although the first DNA methylation inhibitor has been used for more than a decade, we are still just in the beginning of understanding the field of epigenetic therapy. With a better understanding of the DNA methylation landscape and the multi-faceted functions of inhibitors, DNA methylation drugs will evolve from treating merely blood cancers to many other types of solid tumors. Moreover, the combinatory regimens of DNA methylation inhibiting drugs open a new door to cancer therapy and will benefit more patients with better clinical outcomes.

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