Abstract
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 language | English |
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Journal | Cell Metabolism |
Volume | 20 |
Issue number | 2 |
Pages (from-to) | 306-319 |
Number of pages | 14 |
ISSN | 1550-4131 |
DOIs | |
Publication status | Published - 5 Aug 2014 |
Externally published | Yes |
Keywords
- Acetyl Coenzyme A/metabolism
- Acetylation/drug effects
- Brain Neoplasms/metabolism
- Cell Line, Tumor
- Cluster Analysis
- Coenzyme A/metabolism
- Glioma/metabolism
- Glucose/pharmacology
- Histones/metabolism
- Humans
- Interleukin-3/pharmacology
- Male
- Phosphorylation/drug effects
- Prostatic Neoplasms/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- ras Proteins/genetics