SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization
Open accessAbstract
Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates required for biomass generation. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. Mechanistically, SIRT3 mediates metabolic reprogramming by destabilizing hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls glycolytic gene expression. SIRT3 loss increases reactive oxygen species production, leading to HIF1α stabilization. SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1α target genes. Finally, we find that SIRT3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression.
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SIRT3 attenuation of reactive oxygen species production appears to inhibit a glycolytic shift in potentially cancerous cells.
“SIRT3’s attenuation of reactive oxygen species production appears to inhibit a glycolytic shift in potentially cancerous cells ((Finley et al. 2011); (Fan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Finley et al. 2011
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Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models
Komen, J. C., & Thorburn, D. R. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12413 · Cited by 149 · see citing works
<i>Drosophila</i> Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity
Rahman, M., Nirala, N. K., Singh, A., Zhu, L. J., Taguchi, K., Bamba, T., Fukusaki, E., Shaw, L. M., Lambright, D. G., Acharya, J. K., et al. (2014) · Journal of Cell Biology · doi:10.1083/jcb.201404118 · Cited by 116 · see citing works
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A nexus for cellular homeostasis: the interplay between metabolic and signal transduction pathways
Gomes, A. P., & Blenis, J. (2015) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2014.12.007 · Cited by 112 · see citing works
Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients
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Insights into regulators of p53 acetylation
Nagasaka, M., Miyajima, C., Aoki, H., Aoyama, M., Morishita, D., Inoue, Y., & Hayashi, H. (2022) · Cells · doi:10.3390/cells11233825 · Cited by 45 · see citing works
Metabolic reprogramming: a bridge between aging and tumorigenesis
Drapela, S., Ilter, D., & Gomes, A. P. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13261 · Cited by 41 · see citing works
- Authors
- Finley, L. W. S., Carracedo, A., Lee, J., Souza, A., Egia, A., Zhang, J., Teruya-Feldstein, J., Moreira, P. I., Cardoso, S. M., Clish, C. B., Pandolfi, P. P., & Haigis, M. C.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Broad Institute (US)
- Centro de Neurociências e Biologia Celular (PT)
- Corresponding author
- Haigis, Marcia C.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 19
- Issue
- 3
- Pages
- 416-428
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3065720
- OpenAlex
- W2147268550
- Cited by
- 782
- References
- 52
- Citations by year
- 2026: 23 · 2025: 27 · 2024: 49 · 2023: 41 · 2022: 48 · 2021: 54 · 2020: 57 · 2019: 44 · 2018: 57 · 2017: 53 · 2016: 63 · 2015: 60 · 2014: 58 · 2013: 72 · 2012: 57
- FWCI
- 22.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- National Science Foundation
- Alexander and Margaret Stewart Trust
- Glenn Foundation for Medical Research
- National Institutes of Health
- National Institute on Aging (R01AG032375, AG032375)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- SIRT3, HIF-1α, Warburg effect, tumor metabolic reprogramming, glycolysis, protein destabilization, reactive oxygen species, breast cancer, tumor suppression, mitochondrial deacetylase
- MeSH terms
- Animals, Cells, Cultured, Fibroblasts, Glucose, Glycolysis, Humans, Male, Mice, Nude, Neoplasms, Transplantation, Heterologous, Immunoblotting, Cell Hypoxia, Gene Expression, Reactive Oxygen Species, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Metabolomics, Protein Stability, Sirtuin 3, Mice, 129 Strain, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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