Oncometabolites: tailoring our genes

Abstract

Increased glucose metabolism in cancer cells is a phenomenon that has been known for over 90 years, allowing maximal cell growth through faster ATP production and redistribution of carbons towards nucleotide, protein and fatty acid synthesis. Recently, metabolites that can promote tumorigeneis by altering the epigenome have been identified. These 'oncometabolites' include the tricarboxylic acid cycle metabolites succinate and fumarate, whose levels are elevated in rare tumours with succinate dehydrogenase and fumarate hydratase mutations, respectively. 2-Hydroxyglutarate is another oncometabolite; it is produced de novo as a result of the mutation of isocitrate dehydrogenase, and is commonly found in gliomas and acute myeloid leukaemia. Interestingly, the structural similarity of these oncometabolites to their precursor metabolite, α-ketoglutarate, explains the tumorigenic potential of these metabolites, by competitive inhibition of a superfamily of enzymes called the α-ketoglutarate-dependent dioxygenases. These enzymes utilize α-ketoglutarate as a cosubstrate, and are involved in fatty acid metabolism, oxygen sensing, collagen biosynthesis, and modulation of the epigenome. They include enzymes that are involved in regulating gene expression via DNA and histone tail demethylation. In this review, we will focus on the link between metabolism and epigenetics, and how we may target oncometabolite-induced tumorigenesis in the future.

Keywords: cancer; dioxygenase; epigenetics; metabolism; oncometabolites.

Figure 1

Methyl and acetyl transfer pathways. The blue pathway depicts one‐carbon metabolism and its generation of SAM, which provides a methyl group for histone and DNA methylation. Imported folate is reduced to tetrahydrofolate (THF) and subsequently methylated to mTHF by the conversion of serine to glycine and the glycine cleavage system. The folate cycle is coupled to the methionine cycle by mTHF, donating a carbon to homocysteine, converting it to methionine. Adenylation of methionine produces SAM, which acts as a cosubstrate for DNMT and HMT, allowing transfer of its methyl group to DNA and histone tails respectively. The red pathway depicts acetyl transfer from acetyl‐coenzyme A. Acetyl‐coenzyme A, which is derived from pyruvate, links glycolysis to the TCA cycle, but is confined to the mitochondria. In the cytoplasm and nucleus, acetyl‐coenzyme A has to be derived by two alternative methods: first by ACLY, which utilizes citrate from the mitochondrial TCA cycle, and second by ACSS2, which ligates acetate to CoA. Acetyl‐coenzyme A can then be utilized as a cosubstrate by HAT, allowing transfer of the acetyl group to lysines on histone tails. 3‐PG, 3‐phosphoglyceric acid; SAH, S‐adenosylhomocysteine.

Figure 2

αKG‐dependent dioxygenases. This superfamily of enzymes uses oxygen and αKG as cosubstrates, resulting in the hydroxylation of the primary substrate and the decarboxylation of αKG, producing succinate and CO ₂. These enzymes can be inhibited by elevated levels of 2HG, succinate, or fumarate. This occurs by competition with the cosubstrate, αKG, and/or by product inhibition, as for succinate.

Figure 3

Metabolic structure of oncometabolites: Succinate, fumarate and 2HG are closely linked, both structurally and metabolically, to αKG. Succinate and fumarate differ from αKG only by the presence of a hydroxyl group on C2 and the loss of C1. In addition, succinate and fumarate differ only by the presence of an ethylenic bond, which may explain their similar tumorigenic effects. 2HG differs from αKG and glutamate only by the presence of a hydroxyl group instead of a ketone group or amine group, respectively. This explains how 2HG can competitively inhibit αKG by occupying the same enzymatic binding site.