Nur77 Attenuates Phosphoenolpyruvate Carboxykinase Sumoylation To Suppress Hepatocellular Carcinoma Via Promoting Gluconeogenesis

Metabolic reprogramming is one of the important hallmarks of cancer.In recent years,scientists pay more attention to the effect of glycolysis on cancer.However,the correlation between gluconeogenesis and cancer has not been completely clarified.In this study,we used two models of hepatocellular carcinoma(HCC)induced by DEN/CCl4 and HFD/STZ(wild type and Nur77 knock-out mice)and find that Nur77 can significantly inhibit the development of HCC.Low Nur77 expression in clinical HCC samples correlates with poor prognosis.We then identified a key protein-phosphoenolpyruvate carboxykinase 1(PEPCK1)that interacts with Nur77 by mass spectrometry.PEPCK1 is an important limiting enzyme in the gluconeogenesis pathway and plays an inhibitory role in the development of HCC.However,the expression of PEPCK1 was lower in both clinical and liver cancer cells.PEPCK1 can be SUMOylated at lysine 124 and then degraded through the ubiquitin-proteasome pathway.At the same time,the high level expression of acetyltransferase p300 in liver cancer can improve PEPCK1 SUMOylation by increasing its binding with PEPCK1 through acetylation of Ubc9,which further promotes the degradation of PEPCK1,downregulation of gluconeogenesis and upregulation of glycolysis,thereby accelerating the proliferation of liver cancer cells.However,Nur77 not only inhibited the acetylation of Ubc9,but also blocked the interaction of p300 and PEPCK1,thus decreases PEPCK1 SUMOylation and stablizes its protein level,thereby enhancing gluconeogenesis and inhibiting glycolysis.However,It is not possible to inhibit PEPCK1 SUMOylation and degradation because Nur77 was downregulated during the development of hepatocellular carcinoma.Therefore,inhibition of PEPCK1 SUMOylation by Nur77 provides a new direction for the administration of liver cancer.In conclusion,This study illustrates that Nur77 inhibits the development of liver cancer by promoting the process of gluconeogenesis.Thus,gluconeogenesis may act as a unique metabolic barrier to regulate the liver cancer development.The fact that blockage of PEPCK1 SUMOylation and degradation promotes the conversion of aerobic glycolysis to gluconeogenesis may represent another new mechanism to inhibit the progression of liver cancer and provides new strategy for clinical treatment.