Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation

被引：121

作者：

Bian, Xue-li ^{[1
]}

Chen, Hang-zi ^{[1
]}

Yang, Peng-bo ^{[1
]}

Li, Ying-ping ^{[1
]}

Zhang, Fen-na ^{[1
]}

Zhang, Jia-yuan ^{[1
]}

Wang, Wei-jia ^{[1
]}

Zhao, Wen-xiu ^{[2
]}

Zhang, Sheng ^{[2
]}

Chen, Qi-tao ^{[1
]}

Zheng, Yu ^{[1
]}

Sun, Xiao-yu ^{[1
]}

Wang, Xiao-min ^{[2
]}

Chien, Kun-Yi ^{[3
]}

Wu, Qiao ^{[1
]}

机构：

[1] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian Province, Peoples R China

[2] Xiamen Univ, Zhong Shan Hosp, Dept Hepatobiliary Surg, Xiamen 361005, Fujian Province, Peoples R China

[3] Chang Gung Univ, Coll Med, Grad Inst Biomed Sci, Mol Med Res Ctr, Taoyuan 333, Taiwan

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

NEGATIVE REGULATION; NUCLEAR RECEPTORS; COACTIVATOR P300; HIGH EXPRESSION; POOR-PROGNOSIS; ACETYLATION; SNAIL; TRANSCRIPTION; REPRESSION; APOPTOSIS;

D O I：

10.1038/ncomms14420

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

共 64 条

[1] Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase [J].