Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation

Area of Science:

• Molecular Biology
• Cancer Research
• Metabolic Reprogramming

Background:

• Histone acetylation is crucial for gene regulation, DNA replication, and DNA damage response.
• Deregulation of histone acetylation is common in tumors.
• Oncogenic metabolic reprogramming may influence histone acetylation levels in cancer cells.

Purpose of the Study:

• To investigate if cancer cell histone acetylation levels are determined by acetyl coenzyme A (acetyl-CoA) availability.
• To explore the role of oncogenic metabolic reprogramming in modulating histone acetylation.
• To determine the link between glucose availability, acetyl-CoA, and histone acetylation in cancer.

Main Methods:

• Assessed dynamic regulation of acetyl-CoA by glucose availability in cancer cells.
• Measured the ratio of acetyl-CoA to coenzyme A in the nucleus.
• Studied the effects of oncogenic Kras and Akt expression in vivo.
• Investigated Akt's mechanism of action on histone acetylation via ATP-citrate lyase.
• Correlated pAkt(Ser473) levels with histone acetylation marks in human tumor samples.

Main Results:

• Acetyl-CoA levels are dynamically regulated by glucose availability in cancer cells.
• The nuclear acetyl-CoA:coenzyme A ratio modulates global histone acetylation.
• Oncogenic Kras or Akt expression stimulates histone acetylation changes preceding tumor development.
• Akt mediates histone acetylation changes through ATP-citrate lyase.
• pAkt(Ser473) levels significantly correlate with histone acetylation marks in human gliomas and prostate tumors.

Conclusions:

• Acetyl-CoA metabolism is a key determinant of histone acetylation levels in cancer cells.
• Glucose availability and oncogenic signaling pathways (Akt, Kras) significantly impact histone acetylation through acetyl-CoA.
• These findings highlight the role of metabolic reprogramming in cancer epigenetics and suggest potential therapeutic strategies targeting acetyl-CoA metabolism.