乏氧应激诱导烯醇化酶ENO2去戊二酰化修饰调控肝癌细胞代谢和侵袭转移的机制研究

It is well acknowledged that cancer metabolism plays an important role in regulating tumor metastasis and recurrence. In our previous study, ENO2 expression was demonstrated to be closely related to hepatocellular carcinoma (HCC) metastasis. As a key enzyme of glycolysis, ENO2 catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate, but its functional mechanism in HCC still remains unclear. Our previous study found that knockdown of ENO2 significantly inhibited the proliferation and invasion of tumor cells through restraining glycolysis and pentose phosphate pathway. Further studies showed that ENO2 glutarylation was the key factor in the regulation of ENO2 enzyme activity in HCC cells. Moreover, the hypoxia microenvironment of solid tumor might induce SIRT5-mediated ENO2 deglutarylation and activate ENO2 enzyme activity. Based on our previous study, we put forward the hypothesis of ‘hypoxic stress-SIRT5-ENO2 deglutarylation’ axis. Therefore, This study will focus on finding and verifying the specific glutarylation site of ENO2 as well as elucidating the functional mechanism of "hypoxia stress-SIRT5-ENO2 deglutarylation " axis in regulating the invasion and metastasis of HCC. Moreover, we will investigate the correlation between this functional axis and the recurrence, metastasis and poor prognosis of HCC patients. Finally we aim to evaluate the prognostic value and potential targeted interventions for the axis to provide an effective new target for the diagnosis and treatment of HCC.

肿瘤代谢异常在肿瘤转移复发过程中发挥关键作用。课题组前期研究发现烯醇化酶 ENO2 与肝癌转移密切相关。ENO2是糖酵解关键酶，催化2-磷酸甘油酸向磷酸烯醇式丙酮酸转化，然而其在肝癌转移中的功能机制尚未报道。我们的预实验结果表明，ENO2通过调控肝癌细胞糖酵解、PPP循环促进肿瘤细胞增殖与侵袭；进一步研究发现，在肝癌细胞中ENO2戊二酰化修饰是调控其代谢酶活性的关键因素，实体瘤乏氧的微环境可以调控SIRT5介导的ENO2去戊二酰化，激活ENO2酶活性。基于以上基础，我们提出“乏氧应激-SIRT5-ENO2去戊二酰化”调控轴的假设，本课题将围绕这一功能轴寻找并验证影响肝癌侵袭转移的ENO2戊二酰化修饰位点，阐明“乏氧应激- SIRT5-ENO2去戊二酰化” 调控轴在肝癌恶性进展中的功能作用及分子机制，深入挖掘该调控轴潜在的预后预测价值及靶向干预手段，为肝癌诊疗策略提供有效的新靶点。

肿瘤代谢异常在肿瘤转移复发过程中发挥关键作用。课题组前期研究发现烯醇化酶 ENO2 与肝癌转移密切相关。ENO2是糖酵解关键酶，催化2-磷酸甘油酸向磷酸烯醇式丙酮酸转化，然而其在肝癌转移中的功能机制尚未报道。本研究证实抑制ENO2表达显著抑制肝癌细胞糖酵解、PPP循环及肿瘤细胞增殖与侵袭；进一步研究发现，在肝癌细胞中ENO2 K28位点戊二酰化修饰是调控其代谢酶活性的关键因素，SIRT5是调控其去戊二酰化修饰关键酶。实体瘤乏氧的微环境通过抑制SIRT5活性，抑制其介导的ENO2 K28位点去戊二酰化，激活ENO2酶活。深入研究发现“乏氧应激-SIRT5-ENO2去戊二酰化”调控轴通过促进肝癌细胞糖酵解、一碳代谢、PPP循环促进肿瘤生长和转移。本项目阐明“乏氧应激- SIRT5-ENO2去戊二酰化” 调控轴在肝癌恶性进展中的功能作用及分子机制，深入挖掘该调控轴潜在的预后预测价值及靶向干预手段，为肝癌诊疗策略提供有效的新靶点。