| Literature DB >> 24998913 |
Joyce V Lee1,2, Alessandro Carrer1,2, Supriya Shah1,2, Nathaniel W Snyder3, Shuanzeng Wei4, Sriram Venneti5, Andrew J Worth3, Zuo-Fei Yuan6, Hee-Woong Lim7, Shichong Liu6, Ellen Jackson1,2, Nicole M Aiello8,2, Naomi B Haas8, Timothy R Rebbeck9, Alexander Judkins10, Kyoung-Jae Won7, Lewis A Chodosh1,2, Benjamin A Garcia6, Ben Z Stanger8,2, Michael D Feldman4, Ian A Blair3, Kathryn E Wellen1,2.
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.Entities:
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Year: 2014 PMID： 24998913 PMCID： PMC4151270 DOI： 10.1016/j.cmet.2014.06.004
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287