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

• Published in: Nature communications Vol. 8; no. 1; p. 14420
• Main Authors: Bian, Xue-li, Chen, Hang-zi, Yang, Peng-bo, Li, Ying-ping, Zhang, Fen-na, Zhang, Jia-yuan, Wang, Wei-jia, Zhao, Wen-xiu, Zhang, Sheng, Chen, Qi-tao, Zheng, Yu, Sun, Xiao-yu, Wang, Xiao-min, Chien, Kun-Yi, Wu, Qiao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.02.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/51; 13/89; 13/95; 14/105; 38/77; 38/90; 42/70; 631/67/1504/1610/4029; 631/67/2327; 631/80/458/538; 631/80/86/388; Acetylation; Animals; Breast cancer; Carcinogenesis - pathology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell growth; DNA methylation; Down-Regulation - genetics; E1A-Associated p300 Protein - metabolism; Enzyme Stability; Enzymes; Gene expression; Gene Expression Regulation, Neoplastic; Gluconeogenesis; Glucose; Glucose - metabolism; Hep G2 Cells; Hepatitis; Humanities and Social Sciences; Humans; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Metabolic syndrome; Methylation; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; multidisciplinary; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Phosphoenolpyruvate Carboxykinase (ATP) - metabolism; Proteolysis; Roles; Science; Science (multidisciplinary); Snail Family Transcription Factors - metabolism; Sumoylation; Tumor Suppressor Proteins - metabolism; Ubiquitin-Conjugating Enzymes - metabolism; Fujian China; China
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14420

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.