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Acetate Dependence of Tumors
Open accessAbstract
Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.
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“Some cancers are nevertheless dependent on expression of acetyl-CoA synthetase 2 (ACSS2), the cytosolic enzyme that allows cells to synthesize acetyl-CoA from acetate, making this represents a potential therapeutic target (Comerford et al., 2014; Schug et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Comerford et al., 2014
In the citing paper
“Cancer cells are also able to generate acetyl-CoA from cytosolic acetate (Comerford et al., 2014; Gao et al., 2016; Kamphorst et al., 2014; Mashimo et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Comerford et al., 2014
In the citing paper
“Some cancer types, including liver and glioblastomas, readily take up acetate, which can be converted to acetyl-CoA by ACSS and undergo oxidation in the TCA cycle (70, 195).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [195]
In the citing paper
“Specifically, a variety of tumor types localized to the brain, including primary glioblastomas as well as brain metastases that originated from other tissues, have been shown to assimilate exogenous acetate and incorporate acetate-derived carbons into de novo synthesized fatty acids (Comerford et al., 2014; Mashimo et al., 2014; Schug et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Comerford et al., 2014
In the citing paper
“Finally, extracellular acetate has recently been shown to be utilized by some cancers as a source of acetyl-CoA for biosynthesis.”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Comerford et al., 2014
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“Just as the removal of acetyl groups from histones to produce acetate may have a metabolic or signaling function (Comerford et al., 2014; McBrian et al., 2013), here we show how the installation of methyl groups on histones has a fundamental metabolic function that might in some instances supersede a role in transcrip…”
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“ACSS2 was recently found to be important for tumor growth (Schug et al., 2015; Comerford et al., 2014; Mashimo et al., 2014).”
BackgroundInfluentialZhang, C., Wang, X., Zhang, P., He, T.-C., Han, J.-H., Zhang, R., Lin, J., Fan, J., Lu, L., Zhu, W.-W., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04506-4 · Cited by 273
“As a supplement of acetate can regulate the acetyl-CoA level [28], we then treated shACLY group and ACLY Ctrl group with different concentration of acetate, and found that acetylCoA level was elevated dose-dependently (Fig.”
A guide to 13C metabolic flux analysis for the cancer biologist
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Alcohol metabolism contributes to brain histone acetylation
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Metabolic Hallmarks of Metastasis Formation
Elia, I., Doglioni, G., & Fendt, S. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.04.002 · Cited by 253
Targeting the Warburg Effect in Cancer: Where Do We Stand?
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“The identification of alternative energy/building block sources, such as acetate metabolism in some tumors [122,123], emphasizes the complexity and heterogeneity of cancer metabolism.”
The Tumor Metabolic Microenvironment: Lessons from Lactate
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Protein acylation: mechanisms, biological functions and therapeutic targets
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“Besides, two acetyl-CoA-generating enzymes, namely ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain family member 2 (ACSS2), are localized in the nucleus and linked to cell growth and proliferation.(24,25)”
BackgroundThe Warburg effect: a signature of mitochondrial overload
Wang, Y., & Patti, G. J. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.03.013 · Cited by 250
Self-citationMetabolic regulation of chromatin modifications and gene expression
Schvartzman, J. M., Thompson, C. B., & Finley, L. W. S. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201803061 · Cited by 233
“…and in tumors, conversion of acetate to acetyl-CoA by ACSS2 provides an additional source of nucleocytosolic acetyl-CoA and could represent an important recycling mechanism for recapture of acetate after histone deacetylation (Comerford et al., 2014; Schug et al., 2015; Bulusu et al., 2017).”
BackgroundGluconeogenesis in cancer cells – Repurposing of a starvation-induced metabolic pathway?
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Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP
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Acetate Metabolism in Physiology, Cancer, and Beyond
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“Recent studies have also underscored the importance of acetate utilization in tumor cell interactions [25,47,48].”
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“Some of these cancerous tissues incorporate acetate into fatty acids to support biomass production, whereas others have been shown to use acetate to fuel the TCA cycle (Comerford et al., 2014; Kamphorst et al., 2014; Mashimo et al., 2014; Schug et al., 2015).”
BackgroundUndercover: gene control by metabolites and metabolic enzymesPreprint
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“However, multiple enzymes involved in acetyl-CoA synthesis, including ACSS2 and ACLY, have been observed in the nucleus (Takahashi et al. 2006; Wellen et al. 2009; Ariyannur et al. 2010; Comerford et al. 2014).”
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“Acetate is an important fuel in certain cancer cells (Comerford et al., 2014; Mashimo et al., 2014) and in white adipocytes lacking ACLY (Zhao et al.”
Metabolic reprogramming in renal cancer: Events of a metabolic disease
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Emerging role of PI3K/AKT in tumor-related epigenetic regulation
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“The inhibition of tumor growth and failure of glioma self-renewal were found in ACSS2 deficient mice.(42,43) A large number of nonhistone proteins can also be modified by crotonylation in the regulation of subcellular location, cellular composition and function, signal pathways, and biological processes.”
Backgroundp53 genes function to restrain mobile elementsPreprint
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“Immunohistochemistry was performed as previously described (Comerford et al. 2014).”
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Fat and Furious: Lipid Metabolism in Antitumoral Therapy Response and Resistance
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Butyrate enhances CPT1A activity to promote fatty acid oxidation and iTreg differentiation
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“Moreover, inhibiting ACSS2 by its specific inhibitor, 1-(2,3-di(thiophen-2-yl)quinoxalin-6-yl)-3-(2-methoxyethyl)urea (34), completely abrogated of AcCoA and BCoA generation (SI Appendix, Fig.”
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Famine versus feast: understanding the metabolism of tumors in vivo
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“Acetate is converted to acetyl-CoA by the action of acetyl-CoA synthetases (ACSS), and ACSS2 is critical for growth of at least some tumor types in vivo [55].”
Metabolic Signaling to the Nucleus in Cancer
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Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan
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Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress
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Metadata
- Authors
- Comerford, S. A., Huang, Z., Du, X., Wang, Y., Cai, L., Witkiewicz, A. K., Walters, H., Tantawy, M. N., Fu, A., Manning, H. C., Horton, J. D., Hammer, R. E., McKnight, S. L., & Tu, B. P.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Vanderbilt University (US)
- Corresponding author
- McKnight, Steven L.
- Tu, Benjamin P.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 7
- Pages
- 1591-1602
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4272450
- OpenAlex
- W1972254548
- Cited by
- 681
- References
- 57
- Citations by year
- 2026: 32 · 2025: 55 · 2024: 71 · 2023: 68 · 2022: 61 · 2021: 67 · 2020: 52 · 2019: 55 · 2018: 57 · 2017: 59 · 2016: 63 · 2015: 38 · 2014: 3
- FWCI
- 17.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- University of Texas Southwestern Medical Center
- National Heart, Lung, and Blood Institute (P01HL020948)
- National Cancer Institute (P50CA095103, R01CA185169)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- ACSS2, acetyl-CoA synthetase, acetyl-CoA, acetate uptake, cancer metabolism, hepatocellular carcinoma, metabolic vulnerability, histone acetylation, tumor growth
- MeSH terms
- Acetates, Acetyl Coenzyme A, Acetate-CoA Ligase, Animals, Humans, Immunohistochemistry, Liver Neoplasms, Neoplasms, Positron-Emission Tomography, Mice, Triple Negative Breast Neoplasms
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