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Acetyl-CoA metabolism in cancer

Nature Reviews Cancer volume 23, pages 156–172 (2023)Cite this article

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Abstract

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology.

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Fig. 1: Compartmentalized acetyl-CoA production pathways.
Fig. 2: Regulation of acetyl-CoA metabolic enzymes.
Fig. 3: Acetyl-CoA pathways have roles in ferroptosis protection.
Fig. 4: Metabolic regulation of histone acetylation impacts the phenotypes of both cancer cells and non-malignant cells in tumours.

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Acknowledgements

K.E.W. and D.A.G. are supported by the NIDDK of the NIH (R01DK116005). K.E.W. is also supported by the NCI (R01CA228339, R01CA174761, R01CA248315 and R01CA262055) and the Ludwig Institute. D.A.G. is also supported by the NIDDK of the NIH (R01DK094004 and R01DK127175).

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  1. Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA, USA

    David A. Guertin

  2. Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Kathryn E. Wellen

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Glossary

Adipokines

Adipocyte-derived factors released into the blood that can function in an autocrine or paracrine manner to regulate metabolism.

Coenzyme Q

(CoQ). Also known as ubiquinone, an enzyme comprising a redox-active quinone head group and an isoprenoid tail synthesized in the mevalonate pathway that functions as an electron carrier as part of the electron transport chain and as an antioxidant.

De novo lipogenesis

(DNL). The process of building fatty acids from the non-lipid precursor acetyl coenzyme A, which can be generated by a variety of pathways but most commonly from carbohydrates.

Mevalonate pathway

Named after its key intermediate, the five-carbon molecule mevalonate, this pathway generates precursors to a large family of isoprenoids, including cholesterol and coenzyme Q.

M1 and M2 macrophage phenotypes

A classification system in which heterogeneous macrophages are grouped as either M1, which defines activated pro-inflammatory macrophages associated with protection against bacteria and viruses, and M2, which are alternatively activated macrophages that express different markers and are associated with wound healing and immune suppression.

Positron emission tomography tracers

Chemicals than contain a positron-emitting radioisotope that are used to image tumours, for example [18F]fluorodeoxyglucose, a non-metabolizable analogue of glucose that can image tumours with high glucose uptake rates.

Reductive carboxylation

A reductive pathway of glutamine metabolism in which isocitrate dehydrogenase 1 (IDH1) and IDH2 operate in reverse to generate isocitrate and citrate from α-ketoglutarate and CO2.

Stable-isotope tracing

A technique used to follow the metabolic fate of a tracer molecule delivered to cells or tissues, such as [13C]glucose or [13C–15N]glutamine, in which one or more of the abundant and naturally occurring elements — usually C, H or N — are replaced with less abundant, non-radioactive isotopes that can be distinguished in mass by a mass spectrometer.

Statins

Cholesterol-lowering drugs that target 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR).

Thioester bond

A chemical bond that can be summarized as R–CO–S–R′, in which a sulfur instead of oxygen connects the carboxylate ester.

Ubiquitylation

The post-translational modification process of attaching a ubiquitin protein to a lysine residue, which can function as a regulator signal or form polyubiquitin chains targeting a protein for degradation.

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Guertin, D.A., Wellen, K.E. Acetyl-CoA metabolism in cancer. Nat Rev Cancer 23, 156–172 (2023). https://doi.org/10.1038/s41568-022-00543-5

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