Epigenetic Regulators of DNA Cytosine Modification: Promising Targets for Cancer Therapy

Epigenetic modifications are crucial regulators of gene expression that critically impact cell lineage differentiation, survival, and proliferation, and dysregulations are commonly observed in various cancers. The aberrantly modified epigenome confers unique features on tumor cells, including sustained proliferative potential, resistance to growth-suppressive or cell death signals, augmented replicative immortality, invasion, and metastasis. As a result, epigenetic abnormalities exhibit significant impacts on all stages of oncogenesis from its onset to progression to metastasis. Among various epigenetic mechanisms in mammals, DNA cytosine methylation-demethylation is recurrently disrupted in cancers. Due to its inherent reversibility, targeting DNA methylation dynamics has gained tremendous attention as a promising therapeutic option that can ameliorate the effects of cancer-specific epigenetic abnormalities by restoring normal conditions. Various small molecules targeting DNA (de)methylation regulators have been developed as potential cancer therapeutics, some of which are approved for usage in clinics. Clinical trials of many other molecules are underway for both hematological malignancies and solid tumors. In this review, we discuss the DNA methylation/demethylation pathway as a promising target for therapeutic intervention in cancer and highlight the development of various epigenetic drugs targeting DNA-modifying enzymes such as DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes.

Automated summary

Epigenetic modifications play crucial roles in gene expression regulation and are commonly dysregulated in cancers, influencing cell lineage differentiation, survival, and proliferation. Aberrant epigenetic modifications confer unique characteristics to tumor cells, leading to sustained proliferation, resistance to growth-suppressive or cell death signals, replicative immortality, invasion, and metastasis. DNA cytosine methylation-demethylation, among various epigenetic mechanisms in mammals, is frequently disrupted in cancers. Targeting DNA methylation dynamics has gained attention as a promising therapeutic approach to restore normal conditions affected by cancer-specific epigenetic abnormalities. Small molecules targeting DNA (de)methylation regulators have been developed as potential cancer therapeutics, with some already approved for clinical usage and many others undergoing clinical trials.