Akt-dependent metabolic reprogramming regulates tumor cell Histone acetylation

Joyce V. Lee, Alessandro Carrer, Supriya Shah, Nathaniel W. Snyder, Shuanzeng Wei, Sriram Venneti, Andrew J. Worth, Zuo Fei Yuan, Hee Woong Lim, Shichong Liu, Ellen Jackson, Nicole M. Aiello, Naomi B. Haas, Timothy R. Rebbeck, Alexander Judkins, Kyoung Jae Won, Lewis A. Chodosh, Benjamin A. Garcia, Ben Z. Stanger, Michael D. FeldmanIan A. Blair, Kathryn E. Wellen

Research output: Contribution to journalArticlepeer-review

357 Scopus citations


Summary 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.

Original languageEnglish
Pages (from-to)306-319
Number of pages14
JournalCell metabolism
Issue number2
StatePublished - Aug 5 2014


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