title: Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation.
abstract: 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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Xue-Li
authors.initials: XL
authors.lastname: Bian
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Hang-Zi
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Peng-Bo
authors.initials: PB
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Ying-Ping
authors.initials: YP
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Fen-Na
authors.initials: FN
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Jia-Yuan
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Zhong Shan Hospital, Xiamen University, Fujian Province, Xiamen 361005, China.
authors.forename: Wen-Xiu
authors.initials: WX
authors.lastname: Zhao
authors.affiliation: Department of Hepatobiliary Surgery, Zhong Shan Hospital, Xiamen University, Fujian Province, Xiamen 361005, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Qi-Tao
authors.initials: QT
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary Surgery, Zhong Shan Hospital, Xiamen University, Fujian Province, Xiamen 361005, China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Molecular Medicine Research Center, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan.
authors.forename: Kun-Yi
authors.initials: KY
authors.lastname: Chien
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000107:Acetylation; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D004795:Enzyme Stability; D015972:Gene Expression Regulation, Neoplastic; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008745:Methylation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism*; D059748:Proteolysis; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D058207:Sumoylation; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D000071250:Snail Family Transcription Factors; D025521:Tumor Suppressor Proteins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C000597251:PCK2 protein, human; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D000098843:Ubiquitin-Conjugating Enzyme UBC9; D005947:Glucose