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bioRxiv · 10.1101/2020.08.06.240739

Gluconeogenic Enzyme PCK1 Deficiency Is Critical for CHK2 O-GlcNAcylation and Hepatocellular Carcinoma Growth upon Glucose Deprivation

Xiang, J.·Chen, C.·Liu, R.·Gou, D.·Chang, L.·Deng, H.·Gao, Q.·Zhang, W.·Tuo, L.·Pan, X.·Liang, L.·Xia, J.·Huang, L.·Huang, A.·Wang, K.·Tang, N.
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Abstract

Elevated hexosamine-biosynthesis pathway (HBP) activity and O-GlcNAcylation are emerging hallmarks of hepatocellular carcinoma (HCC). Inhibiting O-GlcNAcylation could be a promising anti-cancer strategy. Here, we investigate this possibility and demonstrate that deficiency of phosphoenolpyruvate carboxykinase 1 (PCK1), a rate-limiting enzyme in gluconeogenesis, promotes O-GlcNAcylation and hepatoma cell proliferation under low-glucose conditions. PCK1 loss results in oxaloacetate accumulation and AMPK inactivation, promoting uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) synthesis and CHK2 threonine 378 O-GlcNAcylation and counteracting its ubiquitination and degradation. O-GlcNAcylation also promotes CHK2-dependent Rb phosphorylation and HCC cell proliferation. Therefore, blocking HBP-mediated O-GlcNAcylation suppresses tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation.

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Xiang, J., Chen, C., Liu, R., Gou, D., Chang, L., Deng, H., Gao, Q., Zhang, W., Tuo, L., Pan, X., Liang, L., Xia, J., Huang, L., Huang, A., Wang, K., Tang, N.. 2020-08-06. Gluconeogenic Enzyme PCK1 Deficiency Is Critical for CHK2 O-GlcNAcylation and Hepatocellular Carcinoma Growth upon Glucose Deprivation. https://doi.org/10.1101/2020.08.06.240739

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