Cancer cell metabolism connects epigenetic modifications to transcriptional regulation

Abstract

Adaptation of cellular function with the nutrient environment is essential for survival. Failure to adapt can lead to cell death and/or disease. Indeed, energy metabolism alterations are a major contributing factor for many pathologies, including cancer, cardiovascular disease, and diabetes. In particular, a primary characteristic of cancer cells is altered metabolism that promotes survival and proliferation even in the presence of limited nutrients. Interestingly, recent studies demonstrate that metabolic pathways produce intermediary metabolites that directly influence epigenetic modifications in the genome. Emerging evidence demonstrates that metabolic processes in cancer cells fuel malignant growth, in part, through epigenetic regulation of gene expression programs important for proliferation and adaptive survival. In this review, recent progress toward understanding the relationship of cancer cell metabolism, epigenetic modification, and transcriptional regulation will be discussed. Specifically, the need for adaptive cell metabolism and its modulation in cancer cells will be introduced. Current knowledge on the emerging field of metabolite production and epigenetic modification will also be reviewed. Alterations of DNA (de)methylation, histone modifications, such as (de)methylation and (de)acylation, as well as chromatin remodeling, will be discussed in the context of cancer cell metabolism. Finally, how these epigenetic alterations contribute to cancer cell phenotypes will be summarized. Collectively, these studies reveal that both metabolic and epigenetic pathways in cancer cells are closely linked, representing multiple opportunities to therapeutically target the unique features of malignant growth.

Keywords: DNA methylation; acetylation; acylation; cancer; glycolysis; histone; metabolism; methylation; oxidative phosphorylation.

Figure 1.. Epigenetic modifications linked to cancer cell metabolism.

Cancer cells have increased consumption of glucose for aerobic glycolysis that supports nucleotide and protein synthesis. G6P, glucose-6-phosphate. 3-PG, 3-phosphoglycerate. Ser and Gly is serine and glycine, respectively. One carbon metabolism produces s-adenosyl-methionine (SAM), a required cofactor for DNA methyltransferase (DNMT) and lysine methyltransferase (KMT). The methyltransferase reaction produces S-adenosyl-homocysteine (SAH). Glutamine metabolism supports lipid biosynthesis via the TCA cycle. α-ketoglutarate (α-KG) produced during glutaminolysis is a required cofactor for DNA demethylase TET enzymes and lysine demethylases (KDM). A byproduct of the demethylase reaction is succinate. Mutant isocitrate dehydrogenase (mut IDH) converts α-ketoglutarate to 2-hydroxyglutarate (2-HG), which inhibits demethylase reactions. Acetyl-CoA produced in the TCA cycle and β-oxidation is used by histone acetyltransferases (HAT). Fatty acid β-oxidation is important for membrane synthesis and also produces acyl-CoA that can be used by HATs for additional histone acylation reactions. Neoplastic cells also exhibit oxidative phosphorylation (OxPhos) to produce energy. Class III histone deacetylation (HDAC) reactions by sirtuins require NAD+ produced during oxidative phosphorylation. The deacetylation reaction produces O-acetyl ADP-ribose (OAADR) as a byproduct.