Epigenetics and Cancer Cell Metabolism: Crosstalk and Therapeutic Opportunities

Epigenetics is increasingly recognized to play an important role in tumorigenesis. The epigenome encompasses a multitude of elements that regulate gene expression, including DNA methylation, histone modification, microRNA, and more recently, non-coding RNA. Aberrant regulation of the epigenome has been implicated in altered gene expression and function, which contribute to cancer development and progression via the promotion of cellular transformation, metastatic spread, and drug resistance. Emerging evidence indicates that the activities of key epigenetic regulators including DNA methyltransferases and histone modification enzymes are sensitive to cellular metabolism. The efficiency of these metabolic enzymes depends on the availability of substrates and/or co-factors that can be profoundly altered in cancer. Mutations in metabolic enzymes in cancer also generate oncometabolites that can lead to the dysfunction of DNA and histone demethylases. Conversely, through mediating aberrant expression of genes that are involved in cellular metabolism, epigenetic mechanisms could contribute to metabolic rewiring in cancer to confer a growth advantage to cancer cells. Understanding this cross-talk between epigenetics and cancer cell metabolism may unravel novel therapeutic opportunities. In this chapter, we will review recent discoveries linking epigenetics and cancer cell metabolism, their implications in oncogenesis, and highlight potential approaches to target these cancerspecific abnormities therapeutically.

Keywords: Acetyl-coenzyme A, Cancer, Cancer metabolism, DNA methylation, Epigenetics, Fumarate hydratase, Gene expression, Glutaminolysis, Glycolysis, Histone acetylation, Histone demethylase, Histone methylation, Isocitrate dehydrogenase, MicroRNA, Mitochondrial succinate dehydrogenase, Non-coding RNA, S-adenosylmethionine, TET methyl-cytosine dioxygenase, Tricarboxylic acid cycle, Warburg hypothesis.