Nrf2 Drives Hepatocellular Carcinoma Progression through Acetyl-CoA-Mediated Metabolic and Epigenetic Regulatory Networks

Correlations between the oxidative stress response and metabolic reprogramming have been observed during malignant tumor formation; however, the detailed mechanism remains elusive. The transcription factor Nrf2, a master regulator of the oxidative stress response, mediates metabolic reprogramming in multiple cancers. In a mouse model of hepatocellular carcinoma (HCC), through metabolic profiling, genome-wide gene expression, and chromatin structure analyses, we present new evidence showing that in addition to altering antioxidative stress response signaling, Nrf2 ablation impairs multiple metabolic pathways to reduce the generation of acetyl-CoA and suppress histone acetylation in tumors, but not in tumor-adjacent normal tissue. Nrf2 ablation and dysregulated histone acetylation impair transcription complex assembly on downstream target antioxidant and metabolic regulatory genes for expression regulation. Mechanistic studies indicate that the regulatory function of Nrf2 is low glucose dependent, the effect of which is demolished under energy refeeding. Together, our results implicate an unexpected effect of Nrf2 on acetyl-CoA generation, in addition to its classic antioxidative stress response regulatory activity, integrates metabolic and epigenetic programs to driveHCC progression. Implications: This study highlights that Nrf2 integrates metabolic and epigenetic regulatory networks to dictate tumor progression and that Nrf2 targeting is therapeutically exploitable in HCC treatment.