Metabolic defects provide a spark for the epigenetic switch in cancer.

Cancer is a pathology that is associated with aberrant gene expression and an altered metabolism. Whereas changes in gene expression have historically been attributed to mutations, it has become apparent that epigenetic processes also play a critical role in controlling gene expression during carcinogenesis. Global changes in epigenetic processes, including DNA methylation and histone modifications, have been observed in cancer. These epigenetic alterations can aberrantly silence or activate gene expression during the formation of cancer; however, the process leading to this epigenetic switch in cancer remains unknown. Carcinogenesis is also associated with metabolic defects that increase mitochondrially derived reactive oxygen species, create an atypical redox state, and change the fundamental means by which cells produce energy. Here, we summarize the influence of these metabolic defects on epigenetic processes. Metabolic defects affect epigenetic enzymes by limiting the availability of cofactors like S-adenosylmethionine. Increased production of reactive oxygen species alters DNA methylation and histone modifications in tumor cells by oxidizing DNMTs and HMTs or through direct oxidation of nucleotide bases. Last, the Warburg effect and increased glutamine consumption in cancer influence histone acetylation and methylation by affecting the activity of sirtuins and histone demethylases.