Enolase 1(ENo1)is a glycolytic enzyme involved in tumour progression that performs a variety of classical and nonclassical functions.However,the mechanism by which it promotes tumour progression is still not fully und...Enolase 1(ENo1)is a glycolytic enzyme involved in tumour progression that performs a variety of classical and nonclassical functions.However,the mechanism by which it promotes tumour progression is still not fully understood.Here,we found that ENO1 can bind toβ-site amyloid precursor protein cleaving enzyme 2(BACE2),a codependent gene of ENO1,in liver cancer cells.By suppressing lysosomal-dependent degradation,ENO1 stabilizes BACE2 protein level without affecting its messenger RNA level.Further analysis revealed that ENO1 and BACE2 promote low-density lipoprotein receptor(LDLR)cleavage,leading to decreased absorption of exogenous cholesterol.To maintain intracellular cholesterol levels,ENO1 and BACE2 upregulate the expression of genes involved in de novo cholesterol synthesis through a negative feedback mechanism.Both in vitro and in vivo,BACE2 mediates the tumour-promoting effect of ENO1 in liver cancer.Finally,high expression levels of ENO1 and BACE2 and low expression levels of LDLR were detected in clinical hepatocellular carcinoma samples,and abnormal expression of the ENO1-BACE2-LDLR axis was significantly associated with poor prognosis in patients with liver cancer.These data collectively demonstratedthat ENo1functions in protein cleavage by binding to BACE2 and promotes liver cancer progression by reprogramming cholesterol metabolism.展开更多
基金the National Natural Science Foundation of China(82422057,82273221,and 82341013)Basic Funding of Guangzhou Municipal Science and Technology Bureau(2024A04J6493)the Special Program for Young Scholars of Southern Medical University(G623281133).
文摘Enolase 1(ENo1)is a glycolytic enzyme involved in tumour progression that performs a variety of classical and nonclassical functions.However,the mechanism by which it promotes tumour progression is still not fully understood.Here,we found that ENO1 can bind toβ-site amyloid precursor protein cleaving enzyme 2(BACE2),a codependent gene of ENO1,in liver cancer cells.By suppressing lysosomal-dependent degradation,ENO1 stabilizes BACE2 protein level without affecting its messenger RNA level.Further analysis revealed that ENO1 and BACE2 promote low-density lipoprotein receptor(LDLR)cleavage,leading to decreased absorption of exogenous cholesterol.To maintain intracellular cholesterol levels,ENO1 and BACE2 upregulate the expression of genes involved in de novo cholesterol synthesis through a negative feedback mechanism.Both in vitro and in vivo,BACE2 mediates the tumour-promoting effect of ENO1 in liver cancer.Finally,high expression levels of ENO1 and BACE2 and low expression levels of LDLR were detected in clinical hepatocellular carcinoma samples,and abnormal expression of the ENO1-BACE2-LDLR axis was significantly associated with poor prognosis in patients with liver cancer.These data collectively demonstratedthat ENo1functions in protein cleavage by binding to BACE2 and promotes liver cancer progression by reprogramming cholesterol metabolism.
