Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation.
Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation.
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DOI：
10.1038/ncomms14420
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发表时间：
2017-02-27
影响因子：
16.6
通讯作者：
Wu Q
中科院分区：
文献类型：
--
作者：
Bian XL;Chen HZ;Yang PB;Li YP;Zhang FN;Zhang JY;Wang WJ;Zhao WX;Zhang S;Chen QT;Zheng Y;Sun XY;Wang XM;Chien KY;Wu Q
糖异生是肝细胞的重要代谢过程，在肝细胞癌中表达下调。在这里，我们展示了核受体Nur77是一种肝癌的肿瘤抑制因子，它调节糖异生。临床肝细胞癌样本中Nur77的低表达与预后不良相关，而小鼠的Nur77缺陷促进了肝细胞癌的发展。Nur77与糖异生中的限速酶--磷酸烯醇式丙酮酸羧酸激酶(PEPCK1)相互作用，促进糖异生，抑制糖酵解，导致ATP耗竭和细胞生长停滞。然而，PEPCK1在苏木糖化后变得不稳定，并通过泛素化被泛素偶联酶9(Ubc9)的p300乙酰化增强。尽管Nur77通过削弱p300活性和阻止Ubc9-PEPCK1的相互作用来减弱总合作用并稳定PEPCK1，但由于Snail介导的Nur77启动子的DNA甲基化，Nur77在肝癌样本中被沉默。我们的研究揭示了一种独特的机制，通过拮抗PEPCK1的降解，从糖酵解转换到糖异生来抑制肝癌。在肝细胞癌中，糖异生下调。在这里，作者证明了核受体Nur77通过调节其与相扑结合酶Ubc9的相互作用来增强磷酸烯醇式丙酮酸羧激酶(PEPCK1)的稳定性，从而作为维持糖异生的肿瘤抑制因子。
Gluconeogenesis, an essential metabolic process for hepatocytes, is downregulated in hepatocellular carcinoma (HCC). Here we show that the nuclear receptor Nur77 is a tumour suppressor for HCC that regulates gluconeogenesis. Low Nur77 expression in clinical HCC samples correlates with poor prognosis, and a Nur77 deficiency in mice promotes HCC development. Nur77 interacts with phosphoenolpyruvate carboxykinase (PEPCK1), the rate-limiting enzyme in gluconeogenesis, to increase gluconeogenesis and suppress glycolysis, resulting in ATP depletion and cell growth arrest. However, PEPCK1 becomes labile after sumoylation and is degraded via ubiquitination, which is augmented by the p300 acetylation of ubiquitin-conjugating enzyme 9 (Ubc9). Although Nur77 attenuates sumoylation and stabilizes PEPCK1 via impairing p300 activity and preventing the Ubc9-PEPCK1 interaction, Nur77 is silenced in HCC samples due to Snail-mediated DNA methylation of the Nur77 promoter. Our study reveals a unique mechanism to suppress HCC by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation. Gluconeogenesis is downregulated in hepatocellular carcinoma. Here, the authors show that nuclear receptor Nur77 acts as a tumour suppressor sustaining gluconeogenesis by enhancing phosphoenolpyruvate carboxykinase (PEPCK1) stability via regulating its interaction with the SUMO-conjugating enzyme Ubc9.