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Destabilization of Fatty Acid Synthase by Acetylation Inhibits De Novo Lipogenesis and Tumor Cell Growth
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Abstract
Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacologic inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity, and other diseases. Here, we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin–proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. Our results suggest opportunities to target FASN acetylation as an anticancer strategy. Cancer Res; 76(23); 6924–36. ©2016 AACR.
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“GNPATK128Ac also displayed an increased ability to bind fatty acid synthase FASN (which has also been found to be a target of acetylation-mediated protein homeostasis [59]), an enzyme central to lipogenesis and commonly dysregulated in cancer.”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [59]
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“The GNPATK128Ac-FASN interaction resulted in a repression of TRIM21-mediated FASN degradation [59] and a subsequent increase in FASN, triglyceride, and fatty acids levels consistent with an increase in lipogenesis (Figure 2B).”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [59]
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Cites
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Lysine acetylation targets protein complexes and co-regulates major cellular functions
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Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis
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Regulation of cellular metabolism by protein lysine acetylation
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Self-citationThe growing landscape of lysine acetylation links metabolism and cell signalling
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Orlistat Is a Novel Inhibitor of Fatty Acid Synthase with Antitumor Activity
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Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases
Lahm, A., Paolini, C., Pallaoro, M., Nardi, M. C., Jones, P., Neddermann, P., Sambucini, S., Bottomley, M. J., Lo Surdo, P., Carfı́, A., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706487104 · Cited by 566
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Fatty Acid Synthase As a Potential Therapeutic Target in Cancer
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Bian, X., Liu, R. R., Meng, Y., Xing, D., Xu, D., & Lu, Z. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20201606 · Cited by 1,037
Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention
Butler, L. M., Perone, Y., Dehairs, J., Lupien, L. E., de Laat, V., Talebi, A., Loda, M., Kinlaw, W. B., & Swinnen, J. V. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.07.013 · Cited by 589
Zhong, Q., Xiao, X., Qiu, Y., Xu, Z., Chen, C., Chong, B., Zhao, X., Hai, S., Li, S., An, Z., et al. (2023) · MedComm · doi:10.1002/mco2.261 · Cited by 442
Fatty Acid Synthase: An Emerging Target in Cancer
Fhu, C. W., & Ali, A. (2020) · Molecules · doi:10.3390/molecules25173935 · Cited by 402
Li, W., Li, F., Zhang, X., Lin, H., & Xu, C. S. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00825-8 · Cited by 211
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Metadata
- Authors
- Lin, H.-P., Cheng, Z.-L., He, R.-Y., Song, L., Tian, M.-X., Zhou, L.-S., Groh, B. S., Liu, W.-R., Ji, M.-B., Ding, C., Shi, Y.-H., Guan, K.-L., Ye, D., & Xiong, Y.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- 4State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai, China.
- Beijing Proteome Research Center (CN)
- Fudan University (CN)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Guan, Kun-Liang
- Ye, Dan
- Xiong, Yue
- ORCID
- Venue
- Cancer Research
- Published
- 2016-11-30
- Volume
- 76
- Issue
- 23
- Pages
- 6924-6936
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5135623
- OpenAlex
- W2530450137
- Cited by
- 150
- References
- 51
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 27 · 2023: 26 · 2022: 13 · 2021: 16 · 2020: 19 · 2019: 5 · 2018: 7 · 2017: 3
- FWCI
- 2.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- MOST 973 Program (2012CB910303 and 2012CB910101)
- NSFC (81372198 and 81522033, 81120108016)
- Shanghai Committee of Science and Technology, China (14QA1400600 and 16JC1404000)
- NIH (GM067113 and CA063834, CA196878 and GM51586)
- 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 › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- fatty acid synthase, KAT8, HDAC3, protein acetylation, protein deacetylation, ubiquitin-proteasome degradation, TRIM21, E3 ubiquitin ligase, de novo lipogenesis, tumor cell proliferation, hepatocellular carcinoma, cancer therapy targets
- MeSH terms
- Acetylation, Humans, Signal Transduction, Cell Growth Processes, Cell Proliferation, Lipogenesis, Tumor Microenvironment, Fatty Acid Synthases
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