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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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The emerging hallmarks of cancer metabolism
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“Although a major function of the mitochondria is to provide acetyl-CoA to the cell, cancer cells can also use acetate to support cell growth and survival during metabolic stress (hypoxia or nutrient deprivation) (96, 171).”
BackgroundFrom Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119
“BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
BackgroundThe multifaceted roles of fatty acid synthesis in cancer
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Reprogramming of fatty acid metabolism in cancer
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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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