@article{a3baa8165a5e46e4a7a672436654be93,
title = "Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation",
abstract = "Although cancer cells are frequently faced with a nutrient- and oxygen-poor microenvironment, elevated hexosaminebiosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anticancer strategy. The gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) is downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low-glucose conditions. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo uridine triphosphate synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc synthesis for elevated OGlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-L-norleucine blocked HBP-mediated O-GlcNAcylation and suppressed 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.",
author = "Jin Xiang and Chang Chen and Rui Liu and Dongmei Gou and Lei Chang and Haijun Deng and Qingzhu Gao and Wanjun Zhang and Lin Tuo and Xuanming Pan and Li Liang and Jie Xia and Luyi Huang and Ke Yao and Bohong Wang and Zeping Hu and Ailong Huang and Kai Wang and Ni Tang",
note = "Funding Information: We would like to thank T-C He (University of Chicago) for providing the pAdEasy system and critical reading of the manuscript. We are grateful to Ding Xue (Tsinghua University) for supplying the CRISPR/Cas9 system. We also thank Bing Sun (Shanghai Institute of Biochemistry and Cell Biology) for providing the pLL3.7 vector. We thank Zhimin Lu (Zhejiang University) for suggestions and critical reading of the manuscript. This work was supported by the China National Natural Science Foundation (grants 82073251, 82072286, 81872270, U20A20392), the 111 Project (grant D20028), the Natural Science Foundation Project of Chongqing (grants cstc2018jcyjAX0254, cstc2019jscx-dxwtBX0019, cstc-2019jcyj-msxmX0587), the Major National S&T program (grant 2017ZX10202203-004), the Scientific Research Innovation Project for Postgraduate in Chongqing (grant CYS19191), the Kuanren Talents Program of The Second Affiliated Hospital of Chongqing Medical University, and the Science and Technology Research Program of Chongqing Municipal Education Commission (grants KJZD-M202000401, KJQN201900429). Funding Information: We would like to thank T-C He (University of Chicago) for providing the pAdEasy system and critical reading of the manuscript. We are grateful to Ding Xue (Tsinghua University) for supplying the CRISPR/Cas9 system. We also thank Bing Sun (Shanghai Institute of Biochemistry and Cell Biology) for providing the pLL3.7 vector. We thank Zhimin Lu (Zhejiang University) for suggestions and critical reading of the manuscript. This work was supported by the China National Natural Science Foundation (grants 82073251, 82072286, 81872270, U20A20392), the 111 Project (grant D20028), the Natural Science Foundation Project of Chongqing (grants cstc2018jcyjAX0254, cstc2019jscx-dxwtBX0019, cstc- 2019jcyj-msxmX0587), the Major National S&T program (grant 2017ZX10202203-004), the Scientific Research Innovation Project for Postgraduate in Chongqing (grant CYS19191), the Kuanren Talents Program of The Second Affiliated Hospital of Chongqing Medical University, and the Science and Technology Research Program of Chongqing Municipal Education Commission (grants KJZD-M202000401, KJQN201900429). Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = apr,
day = "15",
doi = "10.1172/JCI144703",
language = "English (US)",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",
}