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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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“Acetic acid is a nutrient that has been found to be a major carbon source for central carbon metabolism in nutrient limited conditions (Comerford et al. 2014).”
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Self-citationTargeting metabolic pathway enhance CAR-T potency for solid tumor
Li, W., Chen, J., & Guo, Z. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113412 · Cited by 9
Pan, D., Bao, Y., Lu, X., Gu, Q., Zhang, Y., & Zheng, Y. (2025) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2025.5655 · Cited by 10
Intestinal acetic acid regulates the synthesis of sex pheromones in captive giant pandas
Zhang, M., Zhang, X., Wang, X., Liu, Y., An, J., Wang, D., Cai, Z.-G., & Hou, R. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1234676 · Cited by 8
Recent advancements in nanomedicine based lipid metabolism for tumour immunotherapy
Zhao, Y., Zhang, X., An, M., Zhang, J., & Liu, Y. (2023) · Journal of drug targeting · doi:10.1080/1061186x.2023.2283829 · Cited by 8
“…transcriptionally up-modulatory by SReBP, is pivotal for acetate catalysation to sustain tumour cells growth, particularly under metabolic stress [15]. lately, accumulating evidence suggests that knockouting AcS2 gene can inhibit the proliferation of cancer cells and the growth of xenograft…”
BackgroundJung, K. H., Lee, S., Kim, H. S., Kim, J., Lee, Y. J., Park, M. S., Seo, M.-S., Lee, M., Yun, M., Park, S., et al. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01185-3 · Cited by 8
Sayed, S. M. E., Baghdadi, H., Ahmed, N. S., Almaramhy, H. H., Mahmoud, A. A.-A., El-Sawy, S. A., Ayat, M., Elshazley, M., Abdel-Aziz, W., Abdel-Latif, H. M., et al. (2018) · Medical Hypotheses · doi:10.1016/j.mehy.2018.11.012 · Cited by 8
“Acetate constitutes a vital supply of acetyl-CoA for feeding these tumors [20].”
BackgroundPerspectives on immunometabolism at the biomaterials interface
Macias, S. L., & Keselowsky, B. G. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.100992 · Cited by 8
Epigenetic roles of lysine-specific demethylase 1 (LSD1) in cancer metabolism
Cheng, B., Xu, X., Fan, B., Ma, T., & Yu, B. (2025) · Drug Discovery Today · doi:10.1016/j.drudis.2025.104397 · Cited by 7
MetaboLM: a metabolomic language model for multi-disease early prediction and risk stratification
Qiu, S., Guo, J., Zhang, Z., Liang, H., You, H., Hu, Y., Liu, G., & Wang, Y. (2025) · Nature Communications · doi:10.1038/s41467-025-66163-3 · Cited by 10
“Speci fi cally, highly glycolytic or hypoxic tumors require suf fi cient acetate as a carbon source to synthesize acetyl-CoA, thereby supporting cell growth and survival under nutrient-limited conditions 39 .”
Self-citationMetabolic reprogramming in colorectal cancer: Mechanisms and therapeutic insights
Xiao, W., Tan, D., Zeng, W., Nie, X., & Wang, M. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102054 · Cited by 8
“62 — 65 Mitochondrial citrate, produced in the Krebs cycle, is exported to the cytoplasm by mitochondrial citrate carrier (CIC, encoded by SLC25A1), where it is essential for the production of de novo FAs.”
Zhu, X., Huang, H., Zou, M., Luo, H., Liu, T., Zhu, S., & Ye, B. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1442723 · Cited by 7
Kalushkova, A., Nylund, P., Párraga, A. A., Lennartsson, A., & Jernberg‐Wiklund, H. (2021) · Epigenomes · doi:10.3390/epigenomes5040022 · Cited by 7
“In these conditions, the predominant source of acetyl-CoA is the catalysation of acetate by acetyl-CoA synthetase (AceCS) in the cytoplasm or mitochondria [243,244] (Figure 3).”
BackgroundMethod(2015) · Journal of Postgenomics Drug & Biomarker Development · doi:10.4172/2153-0769.1000150 · Cited by 7
“The potential difference between the metabolism of normal and cancer cells has recently gained intense interest in the discovery of new targets for cancer treatment [16].”
BackgroundAcetate: Friend or foe against breast tumour growth in the context of obesity?
Yelek, C., Mignion, L., Joudiou, N., Terrasi, R., Gourgue, F., Hul, M. V., Delzenne, N. M., Gallez, B., Corbet, C., Muccioli, G. G., et al. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16034 · Cited by 6
Sun, X. L., Zhou, Z., Chi, X., Cheng, D., Zhang, Y., Xu, Y., Hao, Y., Duan, Y., Li, W., Zhao, Y., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1674838 · Cited by 6
Discovery and mechanism of a highly selective, antifungal acetyl-CoA synthetase inhibitor
Jezewski, A. J., Alden, K. M., Propp, J., Daraji, D. G., Lail, C. L., Heene, M. E., Fuller, A. J., Ferreira, J. C., Liu, L., Battaile, K. P., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64183-7 · Cited by 6
“Overall,acetate-derived AcCoA represents ~10% of the total AcCoA pool in human cells under a normal state of homeostasis, while AcCoA derived from glucose/Acl makes up the majority of the cellular pool 11 .”
InfluentialXia, T., Zhang, L., Sun, G., Yang, X., Zhao, C., & Zhang, H. (2021) · Mammalian Biology · doi:10.1007/s42991-021-00135-0 · Cited by 6
Alcohol-driven metabolic reprogramming promotes development of RORγt-deficient thymic lymphoma
Sun, R., Lei, C., Chen, L., He, L., Guo, H., Zhang, X., Feng, W., Yan, J., McClain, C. J., & Deng, Z. (2022) · Oncogene · doi:10.1038/s41388-022-02257-2 · Cited by 7
“This discovery is consistent with previous studies showing that acetate supports cell proliferation, invasion, and metastases in other cancers[41, 42].”
ResultQiu, X., Lu, R., He, Q., Chen, S., Huang, C., & Lin, D. (2023) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2023151 · Cited by 6
“Presently, acetate has emerged as an alternative energy source for many cancer cells, serving as the primary source of acetyl-CoA under stress conditions [41 ‒ 43], including glioblastoma [44], liver cancer [45], and colorectal cancer [46].”
Sun, N., Zhang, Y., Dong, J., Liu, G., Liu, Z., Wang, J., Qiao, Z., Zhang, J., Duan, K., Nian, X., et al. (2023) · PeerJ · doi:10.7717/peerj.16077 · Cited by 7
“Previous studies have also indicated that β-alanine may be associated with cell energy metabolism and proliferation (Comerford et al., 2014; Li et al., 2018; You et al., 2021).”
Zhang, L., Tan, J. T., Ng, H. Y., Liao, Y., Zhang, R., Chan, K., Hung, I. F., Lam, T. T., & Cheung, K. S. (2024) · Vaccines · doi:10.3390/vaccines12040365 · Cited by 7
“The incomplete reductive TCA cycle utilizes acetyl-CoA derived from acetate, and its upregulation often leads to a consumption of acetate in the gut [56–58].”
BackgroundRole of ATP citrate lyase and its complementary partner on fatty acid synthesis in gastric cancer
Li, C., Liu, W., Liu, Y., Wang, W., & Deng, W. (2024) · Scientific Reports · doi:10.1038/s41598-024-81448-1 · Cited by 6
Sica, V., Pedro, J. M. B., & Kroemer, G. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.07.002 · Cited by 6
Inhibition of the ketolytic acetyl CoA supply to tumors could be their “Achilles heel”
Israël, M., & Schwartz, L. H. (2020) · International Journal of Cancer · doi:10.1002/ijc.32979 · Cited by 6
“Finally, we should point that even with SCOT and ATP citrate lyase inhibition, tumor cells still possess a salvage pathway for making acetyl CoA in the cytosol, from acetate directly taken up and processed by an acetyl CoA synthetase.(9) The enzyme is similar to the one of cholinergic neuromuscular synapses.”
BackgroundMetabolic control of cancer progression as novel targets for therapy
Talukdar, S., Emdad, L., Gogna, R., Das, S. K., & Fisher, P. B. (2021) · Advances in cancer research · doi:10.1016/bs.acr.2021.06.002 · Cited by 6
Haggadone, M. D., Speth, J. M., Hong, H. S., Penke, L. R. K., Zhang, E., Lyssiotis, C. A., & Peters-Golden, M. L. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166458 · Cited by 6
Krencz, I., Vetlényi, E., Dankó, T., Petővári, G., Moldvai, D., Sztankovics, D., Raffay, R. E., Mészáros, K. V., Sebestyén, E., Végső, G., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810587 · Cited by 7
“Additionally, acetyl-CoA production can also be supplied by the acetyl-CoA synthetase utilizing exogenous acetate [11] or can be produced by β-oxidation of fatty acids [12].”
BackgroundYang, R., Ying, G., & Li, B. (2021) · Frontiers of Medicine · doi:10.1007/s11684-021-0866-1 · Cited by 6
Hu, X., Wang, D., Sun, L., Gao, Y., Zhou, D., Tong, X., Li, J., Lin, H. M., Qing, Y., Du, S., et al. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.08.004 · Cited by 7
Differences in glucose concentration shows new perspectives in gastric cancer metabolism
da Silva, E. L., Mesquita, F. P., Portilho, A. J. D. S., Bezerra, E. C. A., Daniel, J. P., Aranha, E. S. P., Farran, S. H., de Vasconcellos, M. C., de Moraes, M. E. A., Moreira-Nunes, C. A., et al. (2022) · Toxicology in Vitro · doi:10.1016/j.tiv.2022.105357 · Cited by 7
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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