期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 8, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI144703
关键词
-
资金
- China National Natural Science Foundation [82073251, 82072286, 81872270, U20A20392]
- 111 Project [D20028]
- Natural Science Foundation Project of Chongqing [cstc2018jcyjAX0254, cstc2019jscxdxwtBX0019, cstc2019jcyjmsxmX0587]
- Major National ST program [2017ZX10202203004]
- Scientific Research Innovation Project for Postgraduate in Chongqing [CYS19191]
- Kuanren Talents Program of The Second Affiliated Hospital of Chongqing Medical University
- Science and Technology Research Program of Chongqing Municipal Education Commission [KJZDM202000401, KJQN201900429]
Cancer cells with elevated HBP activity and O-GlcNAcylation are associated with rapid tumor growth. PCK1 knockout leads to increased O-GlcNAcylation under low-glucose conditions, promoting HCC development. Inhibitors targeting HBP-mediated O-GlcNAcylation could be potential therapeutic targets for HCC treatment.
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 O- GlcNAcylation. 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据