Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation

Lee, Joyce V.; Carrer, Alessandro; Shah, Supriya; Snyder, Nathaniel W.; Wei, Shuanzeng; Venneti, Sriram; Worth, Andrew J.; Yuan, Zuo-Fei; Lim, Hee-Woong; Liu, Shichong; Jackson, Ellen; 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.

doi:10.1016/j.cmet.2014.06.004

Cited by 563Cancer, Lipids, and MetabolismCancer, Hypoxia, and MetabolismHistone Deacetylase Inhibitors Research

Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation

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Lee, Joyce V., Carrer, Alessandro, Shah, Supriya, Snyder, Nathaniel W., Wei, Shuanzeng, Venneti, Sriram, Worth, Andrew J., Yuan, Zuo-Fei +14 more·2014·Cell Metabolism

DOI 10.1016/j.cmet.2014.06.004PMC PMC4151270

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Abstract

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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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.
“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]
Oncogenic activation of the PI3K-AKT signaling axis increases acetyl-CoA levels and promotes elevated histone acetylation both in vitro and in tumors.
“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]
Immunohistochemical analysis of glioblastoma and prostate tumor samples shows Akt activation levels closely correlate with global histone acetylation status.
“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
Glucose- and oncogene-driven increases in global histone acetylation are blocked by ACLY inhibition.
“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
Withdrawal and readdition of glucose, and activation of oncogenic KRAS or Akt, increase total histone acetylation, promoting enhanced and broader gene expression.
“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

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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)
DOI: 10.1016/j.cmet.2014.06.004
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
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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Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation

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