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Acetyl-CoA Synthetase 2 Promotes Acetate Utilization and Maintains Cancer Cell Growth under Metabolic Stress
Open accessAbstract
A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment.
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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 Schug et al., 2015
In the citing paper
“In cancer cells, citrate becomes labeled following supplementation of cells with isotopically labeled acetate ([13C]acetate), indicating that acetate can undergo oxidation in the TCA cycle in cultured cell lines (69).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [69]
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 Schug et al., 2015
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 Schug et al., 2015
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Metadata
- Authors
- Schug, Z. T., Peck, B., Jones, D. T., Zhang, Q., Grosskurth, S., Alam, I. S., Goodwin, L. M., Smethurst, E., Mason, S., Blyth, K., McGarry, L., James, D., Shanks, E., Kalna, G., Saunders, R. E., Jiang, M., Howell, M., Lassailly, F., Thin, M. Z., Spencer-Dene, B., Stamp, G., van den Broek, N. J. F., Mackay, G., Bulusu, V., Kamphorst, J. J., Tardito, S., Strachan, D., Harris, A. L., Aboagye, E. O., Critchlow, S. E., Wakelam, M. J. O., Schulze, A., & Gottlieb, E.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Cancer Research UK (GB)
- John Radcliffe Hospital (GB)
- Babraham Institute (GB)
- AstraZeneca (United Kingdom) (GB)
- Hammersmith Hospital (GB)
- University of Glasgow (GB)
- Corresponding author
- Gottlieb, Eyal
- ORCID
- Schug, Zachary T.
- Peck, Barrie
- Smethurst, Elizabeth
- Mason, Susan
- Blyth, Karen
- McGarry, Lynn
- James, Daniel
- Shanks, Emma
- Jiang, Ming
- Howell, Michael
- Thin, May Zaw
- Stamp, Gordon
- Mackay, Gillian
- Bulusu, Vinay
- Kamphorst, Jurre J.
- Tardito, Saverio
- Strachan, David
- Harris, Adrian L.
- Aboagye, Eric O.
- Critchlow, Susan E.
- Wakelam, Michael J.O.
- Schulze, Almut
- Gottlieb, Eyal
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 27
- Issue
- 1
- Pages
- 57-71
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4297291
- OpenAlex
- W2044515618
- Cited by
- 820
- References
- 73
- Citations by year
- 2026: 64 · 2025: 76 · 2024: 96 · 2023: 72 · 2022: 88 · 2021: 75 · 2020: 63 · 2019: 67 · 2018: 68 · 2017: 57 · 2016: 63 · 2015: 28
- FWCI
- 23.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Funders
- AstraZeneca
- Francis Crick Institute (10009, 10008)
- Cancer Research UK (11359, 18278, 12011, 10337, 16466, 16584, 22311, 18974)
- National Institute for Health and Care Research (NIHR/CS/009/009, NF-SI-0611-10163, EME/13/122/01)
- Directorate for Biological Sciences
- Medical Research Council (MR/J007986/1)
- Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0415, BBS/E/B/000C0413)
- 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
- acetyl-CoA synthetase 2, ACSS2, acetate utilization, cancer cell growth, metabolic stress, hypoxia, lipid depletion, tumor xenografts, fatty acid synthesis, phospholipid synthesis, tumor microenvironment, breast cancer, copy number gain, tumor progression
- MeSH terms
- Acetate-CoA Ligase, Animals, Hypoxia, Fatty Acids, Humans, Mice, Nude, Neoplasm Transplantation, Neoplasms, Stress, Physiological, Gene Expression Regulation, Neoplastic, Disease Progression, Gene Dosage, Cell Line, Tumor, Cell Proliferation, Mice, MCF-7 Cells
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