The Warburg Effect Dictates the Mechanism of Butyrate-Mediated Histone Acetylation and Cell Proliferation
Open accessAbstract
Widespread changes in gene expression drive tumorigenesis, yet our knowledge of how aberrant epigenomic and transcriptome profiles arise in cancer cells is poorly understood. Here, we demonstrate that metabolic transformation plays an important role. Butyrate is the primary energy source of normal colonocytes and is metabolized to acetyl-CoA, which was shown to be important not only for energetics but also for HAT activity. Due to the Warburg effect, cancerous colonocytes rely on glucose as their primary energy source, so butyrate accumulated and functioned as an HDAC inhibitor. Although both mechanisms increased histone acetylation, different target genes were upregulated. Consequently, butyrate stimulated the proliferation of normal colonocytes and cancerous colonocytes when the Warburg effect was prevented from occurring, whereas it inhibited the proliferation of cancerous colonocytes undergoing the Warburg effect. These findings link a common metabolite to epigenetic mechanisms that are differentially utilized by normal and cancerous cells because of their inherent metabolic differences.
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Astrocytes are widely found in postmortem brain tissue, cerebral white matter, and spinal cord of sALS and fALS patients.
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From The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease (2018) · cites this paper as [44]
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Bultman, S. J. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2483 · Cited by 157 · see citing works
Self-citationDiao, H., Jiao, A. R., Yu, B., Mao, X. B., & Chen, D. W. (2019) · Genes & Nutrition · doi:10.1186/s12263-019-0626-x · Cited by 139 · see citing works
The microbiome and its potential as a cancer preventive intervention
Bultman, S. J. (2016) · Seminars in Oncology · doi:10.1053/j.seminoncol.2015.09.001 · Cited by 134 · see citing works
Self-citationAssociation of dietary fibre intake and gut microbiota in adults
Lin, D., Peters, B. A., Friedlander, C., Freiman, H. J., Goedert, J. J., Sinha, R., Miller, G., Bernstein, M. A., Hayes, R. B., & Ahn, J. (2018) · British Journal of Nutrition · doi:10.1017/s0007114518002465 · Cited by 109 · see citing works
Liu, X., Blouin, J.-M., Santacruz, A., Lan, A., Andriamihaja, M., Wilkanowicz, S., Benetti, P.-H., Tomé, D., Sanz, Y., Blachier, F., et al. (2014) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00400.2013 · Cited by 103 · see citing works
Short-Chain Fatty Acids Suppress Inflammatory Reactions in Caco-2 Cells and Mouse Colons
Hung, T. V., & Suzuki, T. (2018) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.7b04233 · Cited by 90 · see citing works
Epigenetics in diabetic nephropathy, immunity and metabolism
Keating, S. T., van Diepen, J. A., Riksen, N. P., & El-Osta, A. (2018) · Diabetologia · doi:10.1007/s00125-017-4490-1 · Cited by 82 · see citing works
Butyrate modulating effects on pro-inflammatory pathways in human intestinal epithelial cells
Elce, A., Amato, F., Zarrilli, F., Calignano, A., Troncone, R., Castaldo, G., & Canani, R. B. (2017) · Beneficial Microbes · doi:10.3920/bm2016.0197 · Cited by 81 · see citing works
Intergenerational Metabolic Syndrome and Neuronal Network Hyperexcitability in Autism
Rivell, A., & Mattson, M. P. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.08.006 · Cited by 50 · see citing works
Effects of valerate on intestinal barrier function in cultured Caco-2 epithelial cell monolayers
Gao, G., Zhou, J., Wang, H., Ding, Y., Zhou, J., Chong, P. H., Zhu, L., Ke, L., Wang, X., Rao, P., et al. (2022) · Molecular Biology Reports · doi:10.1007/s11033-021-06991-w · Cited by 40 · see citing works
Epigenetics in the primary biliary cholangitis and primary sclerosing cholangitis
Cheung, A., LaRusso, N., Gores, G., & Lazaridis, K. (2017) · Seminars in Liver Disease · doi:10.1055/s-0037-1603324 · Cited by 37 · see citing works
Hong, D., Zhang, C., Wu, W., Lu, X., & Zhang, L. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1133546 · Cited by 38 · see citing works
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Roles of Trained Immunity in the Pathogenesis of Cholangiopathies: A Therapeutic Target
Yan, C., Koda, S., Wu, J., Zhang, B., Yu, Q., Netea, M. G., Tang, R., & Zheng, K. (2020) · Hepatology · doi:10.1002/hep.31395 · Cited by 21 · see citing works
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- Authors
- Donohoe, D. R., Collins, L. B., Wali, A., Bigler, R., Sun, W., & Bultman, S. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Bultman, Scott J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 48
- Issue
- 4
- Pages
- 612-626
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3513569
- OpenAlex
- W1994687037
- Cited by
- 993
- References
- 52
- Citations by year
- 2026: 133 · 2025: 94 · 2024: 70 · 2023: 88 · 2022: 89 · 2021: 92 · 2020: 82 · 2019: 68 · 2018: 66 · 2017: 58 · 2016: 67 · 2015: 30 · 2014: 30 · 2013: 24 · 2012: 1
- FWCI
- 10.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 394 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Prevent Cancer Foundation
- American Institute for Cancer Research
- National Institutes of Health (CA125237, P30-ES10126)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Warburg effect, butyrate, histone acetylation, histone deacetylase inhibition, histone acetyltransferase, cell proliferation, colonic epithelial cells, cancer metabolism, acetyl-CoA, epigenetic regulation, colon cancer
- MeSH terms
- Acetylation, Butyrates, Histones, Humans, Models, Biological, Tumor Cells, Cultured, HT29 Cells, HCT116 Cells, Cell Proliferation
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