AMPK‐Dependent Epigenetic Regulation of Metabolism Mediates the Anti‐Cancer Action of Pterostilbene in Hepatocellular Carcinoma

Disrupted metabolism, often implicated in hepatocellular carcinoma (HCC), is linked to aberrant epigenetic patterns. Dietary polyphenols, including pterostilbene (PTS), have been demonstrated to remodel epigenetic landscapes and restore metabolic homeostasis by regulating the activity of AMP‐activated protein kinase (AMPK), a protein recently shown to orchestrate a diverse set of networks to epigenetically mediate transcription. We therefore explored the mechanistic involvement of AMPK in the epigenetic effects of PTS in HCC. We incorporated PTS into a choline‐deficient amino acid defined HCC‐inducing diet (CDAA) in male Fisher‐344 rats and found significant attenuation in HCC development compared to CDAA alone. Transcriptomics by RNA‐sequencing revealed PTS‐upregulated targets, that were enriched in key metabolic processes, including the folate (Aldh1l1), methionine (Bhmt), and sarcosine (Dmdgh) cycles. PTS‐mediated gene upregulation was linked to lower levels of histone H3‐methylation at lysine 27 (H3K27me3) at gene promoters. Mechanistic studies in HCC HepG2 cells revealed that AMPK inhibition abolished epigenetic gene activation in response to PTS, which was accompanied by diminished binding of H3K27me3‐demethylase KDM6A at promoters of PTS‐target genes. Our findings provide evidence for new disease vulnerabilities that arise from epigenetic/metabolic changes and constitute novel opportunities for preventative and therapeutic success in HCC.