Nrf2 drives hepatocellular carcinoma progression through acetyl-CoA-mediated metabolic, epigenetic and oncogenic regulatory networks

Liver tumors had high levels of histone acetylation. Nrf2 knockout mice developed fewer tumors than Nrf2 wild-type mice. The mechanistic study found that Nrf2 knockout reduced the generation of acetyl CoA from impaired glycolysis, TCA cycle, and fatty acid metabolism. Acetyl CoA is the substrate for protein acetylation including histone acetylation. Here we determined the genome-wide distribution of AcH3K27. We found that Nrf2 through regulating acetyl CoA production affects histone acetylation (AcH3K27) to modulate the expression of genes, whose products were involved in the glycolysis, TCA cycle, fatty acid metabolism, and oncogenic Myc/mTor signaling. Our findings supported an Nrf2-integrated metabolic, epigenetic and oncogenic signaling in driving liver tumor development. Overall design: Comparison the genome-wide distribution of histone lysine 27 acetylation in liver tumors of Nrf2 WT (2 samples) and Nrf2 KO mice (2 samples) at 36 weeks of age.