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Akt-Dependent Metabolic Reprogramming Regulates Tumor Cell Histone Acetylation
Open accessAbstract
Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.
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“However, citrate export to the cytosol and subsequent cleavage by ACL provides a major source of cytosolic acetyl-CoA that is the obligate substrate for both de novo lipid synthesis and protein acetylation reactions (39, 187, 188).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [188]
In the citing paper
“Accordingly, oncogenic activation of the PI3K–AKT signaling axis increases acetyl-CoA levels and promotes elevated histone acetylation both in vitro and in tumors (188).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [188]
In the citing paper
“Immunohistochemical analysis of glioblastoma and prostate tumor samples has shown that Akt activation levels closely correlate with global histone acetylation status (Lee et al., 2014).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Lee et al., 2014
In the citing paper
“Furthermore, studies have shown that both the glucose- and oncogene-driven increases in global histone acetylation are blocked by ACLY inhibition (Lee et al., 2014; Wellen et al., 2009).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Lee et al., 2014
In the citing paper
“Indeed, withdrawal and readdition of glucose, as well as activation of oncogenic signaling via introduction of an oncogenic KRAS mutant or a constitutively active form of Akt, increase total histone acetylation, which, in turn, promotes the enhanced and broader gene expression (Lee et al., 2014).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Lee et al., 2014
In the citing paper
“The effect of itaconate on ROS production is consistent with a previous study in zebrafish macrophages, which demonstrated that IRG1 was essential for OXPHOS-driven mtROS production and bactericidal killing172.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [172]
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Metadata
- Authors
- Lee, J. V., Carrer, A., Shah, S., Snyder, N. W., Wei, S., Venneti, S., Worth, A. J., Yuan, Z.-F., Lim, H.-W., Liu, S., Jackson, E., Aiello, N. M., Haas, N. B., Rebbeck, T. R., Judkins, A., Won, K.-J., Chodosh, L. A., Garcia, B. A., Stanger, B. Z., Feldman, M. D., Blair, I. A., & Wellen, K. E.
- Affiliations
- Abramson Cancer Center (US)
- University of Pennsylvania (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Southern California (US)
- Corresponding author
- Wellen, Kathryn E.
- ORCID
- Lee, Joyce V.
- Carrer, Alessandro
- Snyder, Nathaniel W.
- Wei, Shuanzeng
- Venneti, Sriram
- Yuan, Zuo-Fei
- Lim, Hee-Woong
- Liu, Shichong
- Aiello, Nicole M.
- Haas, Naomi B.
- Rebbeck, Timothy R.
- Judkins, Alexander
- Won, Kyoung-Jae
- Chodosh, Lewis A.
- Garcia, Benjamin A.
- Stanger, Ben Z.
- Feldman, Michael D.
- Blair, Ian A.
- Wellen, Kathryn E.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 20
- Issue
- 2
- Pages
- 306-319
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4151270
- OpenAlex
- W2022222857
- Cited by
- 563
- References
- 56
- Citations by year
- 2026: 23 · 2025: 40 · 2024: 51 · 2023: 56 · 2022: 48 · 2021: 68 · 2020: 62 · 2019: 54 · 2018: 41 · 2017: 38 · 2016: 39 · 2015: 30 · 2014: 10
- FWCI
- 12.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- Pew Charitable Trusts
- National Institutes of Health (DP2OD007447)
- National Cancer Institute (R01CA174761, K08CA181475, P30CA016520)
- National Institute of Diabetes and Digestive and Kidney Diseases (R21DK098769, P30 DK 19525, P30DK019525)
- National Institute of Environmental Health Sciences (P30ES0138328, T32ES019851, P30ES013508)
- 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 › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- histone acetylation, acetyl-CoA, metabolic reprogramming, Akt signaling, KRAS, ATP citrate lyase, glucose availability, coenzyme A, glioma, prostate cancer, cancer metabolism, epigenetic regulation
- MeSH terms
- Acetyl Coenzyme A, Acetylation, Brain Neoplasms, Coenzyme A, Glioma, Glucose, Histones, Humans, Interleukin-3, Male, Phosphorylation, Prostatic Neoplasms, Cluster Analysis, ras Proteins, Cell Line, Tumor, Proto-Oncogene Proteins c-akt
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