Metabolic control of epigenetics in cancer

Key Points The histone code is regulated by epigenetic 'readers', 'writers' and 'erasers'. This Review proposes adding to this paradigm the availability of the 'ink' needed to pen chromatin modifications, with the ink being metabolites that are substrates of chromatin-modifying enzymes (that is, for example, acetyl-CoA is the ink for acetyltransferases). This Review puts forward a three-model framework by which metabolism can regulate the epigenome: inhibitor metabolite production; nutrient sensing and chromatin regulation; and localized metabolite production. Metabolic and epigenetic changes are both common features found in all cancer types. Metabolic rewiring in cancer cells provides advantages not only through direct metabolic functions, but also by acting on the epigenetic landscape. Cell signalling has long been known to affect nutrient uptake and use. However, metabolism also feeds back onto signalling pathways to play an active part in major cellular decisions, such as proliferation or differentiation. This reciprocal feedback between cell signalling and metabolism is manipulated in cancer cells to provide growth and survival advantages. Improved understanding of the interplay between cell metabolism and the epigenome will be crucial in designing novel cancer therapeutic strategies. Alterations in the epigenome and metabolism bidirectionally regulate molecular rewiring in cancer cells. This Review discusses how metabolic remodelling can contribute to tumour epigenetic alterations, thereby affecting cancer cell differentiation, proliferation and/or apoptosis as well as therapeutic responses. Alterations in the epigenome and metabolism both affect molecular rewiring in cancer cells and facilitate cancer development and progression. However, recent evidence suggests the existence of important bidirectional regulatory mechanisms between metabolic remodelling and the epigenome (specifically methylation and acetylation of histones) in cancer. Most chromatin-modifying enzymes require substrates or cofactors that are intermediates of cell metabolism. Such metabolites, and often the enzymes that produce them, can transfer into the nucleus, directly linking metabolism to nuclear transcription. We discuss how metabolic remodelling can contribute to tumour epigenetic alterations, thereby affecting cancer cell differentiation, proliferation and/or apoptosis, as well as therapeutic responses.