Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation
Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation
复制标题
糖异生酶 PCK1 缺乏促进 CHK2 O-GlcNAc 酰化和葡萄糖剥夺后肝细胞癌的生长
DOI：
10.1172/jci144703
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发表时间：
2021-04-15
影响因子：
15.9
通讯作者：
Tang, Ni
中科院分区：
文献类型：
--
作者：
Xiang, Jin;Chen, Chang;Tang, Ni
尽管癌细胞经常面临营养和氧气贫乏的微环境，但己糖胺生物合成途径（HBP）活性升高和蛋白质O-GlcNAc化（营养传感器）有助于肿瘤的快速生长，并且是癌症的新标志。抑制O-GlcNAc化可能是一种有前途的抗癌策略。在肝细胞癌（HCC）中，致癌酶磷酸烯醇式丙酮酸羧激酶1（PCK 1）下调。然而，在葡萄糖限制条件下，PCK 1在增强HBP活性和HCC癌变中的潜在作用知之甚少。在这项研究中，PCK 1敲除显著增强了低葡萄糖条件下的整体O-GlcNAc化水平。从机制上讲，PCK 1缺失肝癌细胞中的代谢重编程导致草酰乙酸积累和尿苷三磷酸从头合成增加，有助于尿苷二磷酸-N-乙酰葡萄糖胺（UDP-GlcNAc）生物合成。同时，PCK 1的缺失也导致AMPK-GFAT 1轴失活，促进UDP-GlcNAc合成以提高O-GlcNAc化。值得注意的是，PCK 1的低表达促进CHK 2苏氨酸378 O-GlcNAc化，抵消其稳定性和二聚体形成，增加CHK 2依赖性Rb磷酸化和HCC细胞增殖。此外，氨氧乙酸半盐酸盐和6-重氮-5-氧代-L-正亮氨酸阻断了HBP介导的O-GlcNAc化，并抑制了肝脏特异性Pck 1基因敲除小鼠的肿瘤进展。我们揭示了PCK 1缺失和超-O-GlcNAc化之间的联系，这是HCC肿瘤发生的基础，并提出了通过抑制O-GlcNAc化来治疗HCC的靶点。
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.