氧化应激调控肿瘤细胞LDHA入核的机制研究

Lactate dehydrogenase (LDHA) is a key enzyme involved in anaerobic glycolysis. The classic function of LDHA is to metabolize pyruvate to lactic acid in the cytoplasm; LDHA plays an important role in tumor energy metabolism and is highly expressed in many tumors.. Oxidative stress is an important feature accompanying the development of tumors and plays an important role in the treatment of tumors. Our previous studies have found that in the case of oxidative stress, LDHA can be transferred to the nucleus and play a non-classical metabolic pathway. The production of α-hydroxybutyric acid (αHB), αHB can promote the binding of LDHA and DOT1L, and then regulate the expression of antioxidant-related genes to exert antioxidant function.. However, the mechanism by which LDHA specifically senses oxidative stress and enters the nucleus is not clear. Therefore, this topic focuses on the study of how cytotoxicity of pancreatic cancer in oxidative stress can be used to visually regulate oxidative stress and maintain redox balance in microenvironment; and study oxidative stress on LDHA protein modification. The mechanism of action, as well as the role of nuclear transfer in drug resistance, to further understand the molecular mechanism of metabolites and tumor microenvironment in tumorigenesis and explore new targets for tumor therapy from tumor metabolism.

乳酸脱氢酶（LDHA）是参与无氧糖酵解的关键酶，经典的功能是在细胞质中代谢丙酮酸成乳酸；LDHA在肿瘤的能量代谢中有重要作用，在很多肿瘤中显著高表达。. 氧化应激是伴随肿瘤发生发展的重要特点，在肿瘤的治疗中也有重要的作用；我们的前期研究发现，肿瘤细胞在氧化应激的情况下，LDHA可以转移至细胞核，发挥非经典的代谢途径产生α羟基丁酸（αHB），αHB能够促进LDHA与DOT1L结合，进而调控抗氧化相关基因的表达发挥抗氧化功能。. 然而LDHA具体如何感知氧化应激并进入细胞核的机制并不清楚。因此本课题着重于研究胰腺癌在氧化应激情况下，肿瘤细胞如何通过LDHA感知氧化应激来表观调控氧化应激，维持微环境的氧化还原平衡；并研究其中氧化应激对LDHA蛋白修饰的作用机制，以及其核转移在肿瘤治疗耐药中的作用，进一步理解代谢物和肿瘤微环境在肿瘤发生发展的分子机制，从肿瘤代谢方面探寻肿瘤治疗的新靶点

LDHA在肿瘤代谢中的作用很重要，但关于LDHA定位于胞质，其转位细胞核的机制和功能鲜有研究。本项目从这一点出发，发现了精氨酸的饥饿是促进LDHA入核的关键信号，进一步的通过CRISPR全基因组筛选发现PIAS是介导精氨酸影响LDHA入核的关键蛋白。这一研究结果揭示了氨基酸代谢与LDHA之间的关联，为后续研究提供了基础。