This review provides a brief overview of the basic principles of epigenetic gene regulation and then focuses on recent development of epigenetic drugs for
cancer treatment and prevention with an emphasis on the molecular mechanisms of action. The approved epigenetic drugs are either inhibitors of
DNA methyltransferases or
histone deacetylases (HDACs). Future epigenetic drugs could include inhibitors for
histone methyltransferases and
histone demethylases and other epigenetic
enzymes. Epigenetic drugs often function in two separate yet interrelated ways. First, as epigenetic drugs per se, they modulate the epigenomes of premalignant and malignant cells to reverse deregulated epigenetic mechanisms, leading to an effective therapeutic strategy (epigenetic
therapy). Second, HDACs and other epigenetic
enzymes also target non-
histone proteins that have regulatory roles in cell proliferation, migration and cell death. Through these processes, these drugs induce
cancer cell growth arrest, cell differentiation, inhibition of
tumor angiogenesis, or cell death via apoptosis,
necrosis, autophagy or mitotic catastrophe (
chemotherapy). As they modulate genes which lead to enhanced chemosensitivity, immunogenicity or dampened innate
antiviral response of
cancer cells, epigenetic drugs often show better efficacy when combined with
chemotherapy,
immunotherapy or
oncolytic virotherapy. In
chemoprevention,
dietary phytochemicals such as
epigallocatechin-3-gallate and
sulforaphane act as epigenetic agents and show efficacy by targeting both
cancer cells and the tumor microenvironment. Further understanding of how epigenetic mechanisms function in
carcinogenesis and
cancer progression as well as in normal physiology will enable us to establish a new paradigm for intelligent
drug design in the treatment and prevention of
cancer.