RNA-Seq of PCK1 knockout in PLC/PRF/5

Deciphering the crosstalk between metabolism reprogramming and epigenetic regulation has become a promising strategy for cancer therapy. Here, we discovered that gluconeogenic enzyme PCK1 fuels the generation of S-adenosylmethionine (SAM) through the serine synthesis pathway. Increased SAM, catalyzed by methyltransferase SUV39H1, serves as methyl donor to support the H3K9me3 modification for S100A11 suppression. Mechanically, PCK1 deficiency-induced oncogenic activation of S100A11 is due to the interaction with AKT1 to upregulate PI3K/AKT signaling. Intriguingly, hepatocellular carcinoma progression driven by PCK1-deficiency was suppressed by SAM supplement or S100A11-knockout in vivo and in vitro. These findings reveal that the availability of key metabolite SAM as a bridge connecting gluconeogenic enzyme PCK1 and H3K9 trimethylation in blunting HCC progression, thus suggesting a potential therapeutic strategy against HCC.