Acetate can be used by tumour cells as an important bioenergetic fuel or as a nutritional source to support lipid biosynthesis.
Acetate can be a precursor for acetylation of histones and other proteins and hence can serve as an epigenetic and post-translational modifier.
Despite the low circulating concentration of acetate, acetate may still exert its effects through intra- and intercellular recycling of acetate molecules within the tumour microenvironment or at sites with high local acetate concentrations.
Acetyl-CoA synthetase 2 (ACSS2) is emerging as an important enzyme in the growth of many different types of cancers and is induced by cancer cells in response to nutrient stress conditions. Targeting ACSS2 may prove to be a powerful therapeutic modality.
ACSS2 is highly upregulated in multiple cancer types and may be a useful biomarker for anti-ACSS2 therapies.
[11C]acetate has demonstrated excellent potential as an alternative positron emission tomography imaging probe for cancer. More studies on why some but not other tumours are [11C]acetate avid, and correlating these data with the expression of acetyl-CoA synthetases will aid in deciphering the exact manner by which acetate metabolism supports tumour growth and help in stratifying patients for future anti-ACSS2 therapy.
Recent high-profile reports have reignited an interest in acetate metabolism in cancer. Acetyl-CoA synthetases that catalyse the conversion of acetate to acetyl-CoA have now been implicated in the growth of hepatocellular carcinoma, glioblastoma, breast cancer and prostate cancer. In this Review, we discuss how acetate functions as a nutritional source for tumours and as a regulator of cancer cell stress, and how preventing its (re)capture by cancer cells may provide an opportunity for therapeutic intervention.
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MetaboMed Ltd, Israel, Shareholder and Director (E.G.). Z.T.S. and J.V.V. declare no competing interests.
- Crabtree effect
The phenomenon whereby aerobic fermentation of glucose occurs and respiration is inhibited if the glucose concentration surpasses a threshold value.
- Short-chain fatty acids
(SCFAs). Fatty acids with an aliphatic tail of two to six carbon atoms. The SCFAs acetate, propionate and butyrate are abundantly produced by bacterial fermentation of dietary carbohydrates in the colon.
- Facultative autotrophs
Organisms that can grow using organic carbon but are also able to assimilate organic carbon from inorganic carbon sources such as CO2.
- Lipogenic substrate gap
Alternative carbon sources that contribute to de novo fatty acid synthesis, as a large proportion (20–40%) of carbons in fatty acids in hypoxic cancer cells cannot be attributed to glucose or glutamine.
- Bioenergetic substrate gap
Alternative sources of carbon that contribute to tumour bioenergetics, as less than 50% of acetyl-CoA in human brain tumours is derived from blood-borne glucose.
A post-translational modification of histone lysine residues that has been shown to stimulate transcription and is, at least partially, dependent on acetyl-CoA synthetase 2 (ACSS2)-catalysed production of crotonyl-CoA from the short-chain fatty acid crotonate.
- Caloric restriction
Caloric restriction without malnutrition is a dietary strategy that has been studied extensively as a way to slow ageing and extend lifespan.
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Schug, Z., Vande Voorde, J. & Gottlieb, E. The metabolic fate of acetate in cancer. Nat Rev Cancer 16, 708–717 (2016). https://doi.org/10.1038/nrc.2016.87
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