title: Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation.
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.
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.|Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Joyce V
authors.initials: JV
authors.lastname: Lee
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.|Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Carrer
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.|Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Supriya
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Snyder
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Shuanzeng
authors.initials: S
authors.lastname: Wei
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA 10065.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.affiliation: Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Worth
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Zuo-Fei
authors.initials: ZF
authors.lastname: Yuan
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Hee-Woong
authors.initials: HW
authors.lastname: Lim
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Shichong
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.|Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Ellen
authors.initials: E
authors.lastname: Jackson
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.|Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Aiello
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Naomi B
authors.initials: NB
authors.lastname: Haas
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Judkins
authors.affiliation: Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.|Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.|Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.affiliation: Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.|Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wellen
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003065:Coenzyme A / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D007377:Interleukin-3; D000105:Acetyl Coenzyme A; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins; D005947:Glucose; D003065:Coenzyme A