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Cell Metab. 2014 Aug 5;20(2):306-319. doi: 10.1016/j.cmet.2014.06.004. Epub 2014 Jul 3.

Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation.

Author information

1
Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
2
Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
3
Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
4
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
5
Memorial Sloan Kettering Cancer Center, New York, NY, USA 10065.
6
Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
7
Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
8
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
9
Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
10
Department of Pathology and Laboratory Medicine, Keck School of Medicine of University of Southern California and Children's Hospital Los Angeles, Los Angeles, CA, USA 90027.
#
Contributed equally

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.

PMID:
24998913
PMCID:
PMC4151270
DOI:
10.1016/j.cmet.2014.06.004
[Indexed for MEDLINE]
Free PMC Article

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