The Bidirectional Relationship Between Cancer Epigenetics and Metabolism

Abstract

Metabolic and epigenetic reprogramming are characteristics of cancer cells that, in many cases, are linked. Oncogenic signaling, diet, and tumor microenvironment each influence the availability of metabolites that are substrates or inhibitors of epigenetic enzymes. Reciprocally, altered expression or activity of chromatin-modifying enzymes can exert direct and indirect effects on cellular metabolism. In this article, we discuss the bidirectional relationship between epigenetics and metabolism in cancer. First, we focus on epigenetic control of metabolism, highlighting evidence that alterations in histone modifications, chromatin remodeling, or the enhancer landscape can drive metabolic features that support growth and proliferation. We then discuss metabolic regulation of chromatin-modifying enzymes and roles in tumor growth and progression. Throughout, we highlight proposed therapeutic and dietary interventions that leverage metabolic-epigenetic cross talk and have the potential to improve cancer therapy.

Keywords: cancer; cell metabolism; chromatin modification; epigenetics.

Figure 1

Metabolic and epigenetic reprogramming in cancer cells exert reciprocal regulation on one another. The tumor microenvironment, oncogenic signaling, and systemic metabolism, including the individual’s diet, each influence the availability of metabolites utilized by epigenetic enzymes. Tumor epigenetic features can reciprocally drive changes in the expression of genes that impact cancer metabolism. Figure adapted from images created in Biorender. Abbreviations: Ac, acetylation; Me, methylation; TF, transcription factor.

Figure 2

Deficiency in epigenetic enzymes alters expression of metabolic genes. (a) BCAT1 expression is suppressed by histone methylation. Loss of repressive histone methylation occurs with EZH2 deficiency, as well as some cancers treated with sublethal tyrosine kinase inhibition. BCAT1 catalyzes the reversible transamination of BCAAs to BCKAs using αKG as an amino group acceptor and glutamate as an amino group donor. The substrates and products of the reaction catalyzed by BCAT1 impact the generation of downstream metabolites such as GSH and impinge on TET2 and mTORC1 activity. (b) The system x_c⁻ cysteine-glutamate antiporter is a dimer of SLC7A11 and SLC3A2. Expression levels of SLC7A11 are regulated by ARID1A and BAP1. System x_c⁻ transports intracellular cystine, which is needed to synthesize glutathione. Figure adapted from images created in Biorender. Abbreviations: αKG, alpha-ketoglutarate; BCAAs, branched-chain amino acids; BCKAs, branched-chain alpha-keto acids; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; GSSG,oxidized glutathione; PPP, pentose phosphate pathway; ROS, reactive oxygen species.

Figure 3

Oncogenic signaling and diet impact one-carbon metabolism and methylation. One-carbon metabolism is composed of folate metabolism and the methionine cycle and is important for DNA synthesis and the SAM production needed for methylation reactions. Dietary availability of serine, folate, and methionine, as well as oncogenic signaling and microenvironmental nutrient availability, can impact the serine-glycine one-carbon network, leading to epigenetic alterations and exposing therapeutic vulnerabilities. Figure adapted from images created in Biorender. Abbreviations: 3-PGA, 3-phosphoglyceric acid; 3PHP, 3-phosphohydroxypyruvate; 3PSer, 3-phosphoserine; dcSAM, decarboxylated SAM; GSH, glutathione; MTA, methylthioadenosine; MTAP, MTA phosphorylase; PHGDH, phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate.