Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth
Open accessAbstract
Increased fatty acid synthesis is required to meet the demand for membrane expansion of rapidly growing cells. ATP-citrate lyase (ACLY) is upregulated or activated in several types of cancer, and inhibition of ACLY arrests proliferation of cancer cells. Here we show that ACLY is acetylated at lysine residues 540, 546, and 554 (3K). Acetylation at these three lysine residues is stimulated by P300/calcium-binding protein (CBP)-associated factor (PCAF) acetyltransferase under high glucose and increases ACLY stability by blocking its ubiquitylation and degradation. Conversely, the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY. Substitution of 3K abolishes ACLY ubiquitylation and promotes de novo lipid synthesis, cell proliferation, and tumor growth. Importantly, 3K acetylation of ACLY is increased in human lung cancers. Our study reveals a crosstalk between acetylation and ubiquitylation by competing for the same lysine residues in the regulation of fatty acid synthesis and cell growth in response to glucose.
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High glucose concentrations result in ACLY acetylation at K540, K546, and K554, which block ubiquitination at these sites and increase ACLY stability by preventing UBR4-mediated degradation.
“High glucose concentrations result in ACLY acetylation at three lysine residues (K540, K546, K554), which function to block ubiquitination at these sites and thus increase ACLY stability by preventing ubiquitin-mediated degradation via E3 ligase UBR4 [42].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [42]
ACLY stability can vary with glucose concentrations via acetylation-mediated stabilization.
“ACLY stability can vary with glucose concentrations via acetylation-mediated stabilization [42].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [42]
ACLY acetylation enhances cell proliferation through increased ACLY function, resulting in increased acetyl-CoA production and lipogenesis.
“ACLY acetylation enhances cell proliferation through an increase in ACLY function, resulting in increased acetyl-CoA production and lipogenesis [42,43].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [42]
This regulatory mechanism is enacted by the acetyltransferase PCAF and deacetylase SIRT2, which modulate ACLY acetylation state in response to glucose levels.
“This regulatory mechanism is enacted by acetyltransferase and deacetylase pair PCAF and SIRT2, which are responsible for modulating ACLY acetylation state in response to glucose levels [42].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [42]
ACLY acetylation at these sites is upregulated in various lung cancers, indicating that tumorigenic mechanisms could take advantage of acetylation-mediated aberrant ACLY function to fuel growth.
“ACLY acetylation at these sites is upregulated in various lung cancers- indicating that tumorigenic mechanisms could be taking advantage of acetylation-mediated aberrant ACLY function to fuel growth [42].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [42]
The connection between nutrient supplementation and acetylation of metabolic proteins exemplified by BCAT2, PHGDH, and GS has been shown before with ACLY, MATIIα, ECHS1, and splicing factors.
“The connection between nutrient supplementation and acetylation of metabolic proteins exemplified by BCAT2, PHGDH, and GS is a concept that has been shown before with ACLY [42], methionine adenosyltransferase IIα (MATIIα) [67], enoyl-CoA hydratase-1 (ECHS1) [68], and splicing factors that function to regulate glucose metabolism [69]”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [42]
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References 37 · Cited by 384
- Authors
- Lin, R., Tao, R., Gao, X., Li, T., Zhou, X., Guan, K.-L., Xiong, Y., & Lei, Q.-Y.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Lei, Qun-Ying
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 51
- Issue
- 4
- Pages
- 506-518
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4180208
- OpenAlex
- W2168921982
- Cited by
- 384
- References
- 37
- Citations by year
- 2026: 28 · 2025: 32 · 2024: 35 · 2023: 36 · 2022: 39 · 2021: 31 · 2020: 39 · 2019: 23 · 2018: 23 · 2017: 16 · 2016: 33 · 2015: 27 · 2014: 19 · 2013: 2
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- UNC Libraries
- Funders
- Shanghai Key Basic Research Program
- National Natural Science Foundation of China (NCET-09, 2012CB910101, 81071744, 81225016)
- Tongji University
- National Institutes of Health
- Program for New Century Excellent Talents in University
- Shanghai Leading Academic Discipline Project
- National Cancer Institute (R01CA068377, R01CA163834)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- ATP citrate lyase, protein acetylation, lysine acetylation, protein stability, ubiquitination, fatty acid synthesis, lipogenesis, tumor growth, glucose metabolism, lung cancer, cell proliferation
- MeSH terms
- p300-CBP-Associated Factor, Acetylation, Animals, ATP Citrate (pro-S)-Lyase, Calmodulin-Binding Proteins, Cytoskeletal Proteins, Fatty Acids, Humans, Immunoenzyme Techniques, Lung Neoplasms, Male, Mice, Nude, Protein Processing, Post-Translational, RNA, Messenger, Tumor Cells, Cultured, Blotting, Western, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitin, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Cell Proliferation, p300-CBP Transcription Factors, Mice, Ubiquitination, Sirtuin 2, Real-Time Polymerase Chain Reaction
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