Title: Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation.
Authors: 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
Published In Cell Metab, (2014 Aug 05)
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.
PubMed ID: 24998913
MeSH Terms: Acetyl Coenzyme A/metabolism; Acetylation/drug effects; Brain Neoplasms/metabolism; Brain Neoplasms/pathology; Cell Line, Tumor; Cluster Analysis; Coenzyme A/metabolism; Glioma/metabolism; Glioma/pathology; Glucose/pharmacology; Histones/metabolism*; Humans; Interleukin-3/pharmacology; Male; Phosphorylation/drug effects; Prostatic Neoplasms/metabolism; Prostatic Neoplasms/pathology; Proto-Oncogene Proteins c-akt/metabolism*; ras Proteins/genetics; ras Proteins/metabolism