Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation

Although cancer cells are frequently faced with a nutrient- and oxygen-poor microenvironment, elevated hexosamine-biosynthesis pathway (HBP) activity protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor emerging hallmarks cancer. Inhibiting could be promising anticancer strategy. The gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) is downregulated in hepatocellular carcinoma (HCC). However, little known about the potential role PCK1 enhanced HBP HCC carcinogenesis under glucose-limited conditions. In this study, knockout markedly global levels low-glucose Mechanistically, metabolic reprogramming PCK1-loss hepatoma led oxaloacetate accumulation increased de novo uridine triphosphate synthesis contributing diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion also resulted AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc for O-GlcNAcylation. Notably, lower expression promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability dimer formation, increasing CHK2-dependent Rb phosphorylation cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride 6-diazo-5-oxo-L-norleucine blocked HBP-mediated suppressed progression liver-specific Pck1-knockout mice. We reveal link between depletion hyper-O-GlcNAcylation that underlies oncogenesis suggest therapeutic targets act by inhibiting