肿瘤糖代谢关键基因LDHA的调控网络研究

肿瘤细胞有氧糖酵解（Warburg效应）是肿瘤标志性特征之一。LDHA是糖酵解最后一步反应的关键酶，是糖酵解途径的关键检查点，在肿瘤发生发展中起重要作用，但LDHA的调控机制还有待阐明。我们的初步研究结果表明，LDHA与E3泛素连接酶TRIM58、去泛素化酶OTUB1、转录因子FOXO3a等存在相互作用，进一步分析发现LDHA可能存在新的表达调控方式和新的功能及机制。本研究拟在此基础上，在有或无应激条件作用下，利用多种蛋白质间相互作用技术进一步确定LDHA与上述这些候选蛋白之间的相互作用及其结合结构域，阐明LDHA蛋白降解机制，利用报告基因、RNA-seq、ChIP、ChIP-seq等技术阐明LDHA对转录因子的转录调节作用及其机制，在细胞、动物、临床标本中确定LDHA调控轴对糖代谢、肿瘤生长和转移的影响及其临床意义，为阐明糖代谢机制及靶向糖代谢通路开发抗肿瘤药物提供新的依据和靶标。

Aerobic glycolysis (Warburg effect) of cancer cells is one of the hallmarks of cancer. LDHA is the key enzyme in the last step of glycolysis reaction, is the key checkpoint of glycolytic pathway and plays an important role in the development and progression of cancer. However, the regulatory mechanism of LDHA remains to be clarified. Our preliminary results showed that LDHA interacted with the E3 ubiquitin ligase TRIM58, the deubiquitinase OTUB1, the transcription factor FOXO3a, etc. Further analysis indicates that LDHA may have new expression regulation modes and new functions and mechanisms. Based on these observations, we will further determine the interaction between LDHA and the above-mentioned candidate proteins as well as their binding domains with or without stress, using different protein-protein interaction techniques, and will elucidate mechanisms of LDHA protein degradation. By use of reporter genes, RNA-seq, ChIP, ChIP-seq and other technologies, we will clarify roles and mechanisms of LDHA in the transcription factor-mediated transcriptional regulation. We will determine the effects of LDHA regulatory axis on glucose metabolism, tumor growth, and metastasis as well as its clinical significance, in cells, animals, and clinical specimens. This study will provide new basis and targets for elucidating glucose metabolism mechanisms and targeting glucose metabolism pathway to develop anti-tumor drugs.