甘油醛-3-磷酸脱氢酶精氨酸甲基化调控在肿瘤中的作用及其分子机制研究

Glyceraldehyde -3- phosphate dehydrogenase enzyme (GAPDH) is one of the most important enzymes involved in cellular energy metabolism. GAPDH plays an important role in glycolytic pathway, glucose metabolic flux and flow direction. GAPDH regulates tumor metabolism and is closely associated with the development and progression of various cancers. Recent studies reported that GAPDH dynamically translocated to nucleus, mitochondria and other organelles, and participated in multiple cellular process, such as cell death, cell aging, and so on. We presently show that 234 arginine residue (R234) of GAPDH protein is modified by methylation. Further experiments determined that R234 is asymmetrically di-methylated. The methylation modification at R234 inhibits the enzyme activity of GAPDH. We speculate that arginine methylation at R234 might regulate the stability, polymerization and subcellular localization of GAPDH. Based on GAPDH is associated with tumorigenesis and tumor development, and GAPDH is an essential enzyme, even an important regulator in cells, GAPDH is a potential target for cancer therapy. Our study can provide not only the insight into tumor metabolism and cancer development, but also the new target for cancer therapy.

甘油醛-3-磷酸脱氢酶 (glyceraldehyde-3-phosphate dehydrogenase, GAPDH) 在糖酵解途径中起着承上启下的作用，对调控葡萄糖代谢流的导向和流量具有重要意义。GAPDH调控肿瘤代谢，与多种肿瘤的发生和恶性发展相关。近年研究发现，GAPDH可动态分布至细胞核、线粒体等细胞器，参与细胞死亡、细胞衰老等过程，在肿瘤的发生发展中具有复杂的功能。我们首次证明GAPDH蛋白234位精氨酸残基（R234）受甲基化修饰，进一步实验确定GAPDH R234的修饰类型主要为非对称性二甲基化，且该甲基化修饰抑制GAPDH的酶活性。我们继续研究精氨酸甲基化调控GAPDH酶活性和功能的机制，探讨GAPDH精氨酸甲基化在肿瘤发生发展中的作用，不仅能够补充肿瘤代谢的重要内容、拓展对肿瘤的理解，而且可以为肿瘤的治疗提供潜在的靶分子，具有重要的重要的理论和实践意义。

甘甘油醛-3-磷酸脱氢酶 (glyceraldehyde-3-phosphate dehydrogenase, GAPDH) 是细胞能量代谢链中最重要的酶之一，尽管GAPDH长期被认为是一个管家蛋白，近期研究表明 GAPDH在肿瘤中发生异常表达，与多种肿瘤的发生和恶性发展相关。GAPDH在糖酵解途径中起着承上启下的作用，对调控葡萄糖代谢流的导向和流量具有重要意义。本项目发现GAPDH受甲基化修饰；精氨酸甲基转移酶1（CARM1）在精氨酸234（R234）位点甲基化GAPDH，从而抑制GAPDH催化活性；葡萄糖饥饿上调CARM1，诱导GAPDH R234高甲基化、抑制GAPDH活性，降低糖酵解流量，抑制肿瘤细胞增殖；在临床肝细胞癌标本中，GAPDH R234表现为低甲基化，且GAPDH R234甲基化与CARM1蛋白呈正相关。通过以上一系列的研究，阐释了GAPDH甲基化在肿瘤发生发展中的作用及其作用机制，揭示了肿瘤细胞感受营养变化从而调整代谢方式的新机制。.本项目主要研究代谢酶和肿瘤相关分子，探讨其调控机制及在消化道肿瘤发生发展中的作用，项目涉及肝癌、结直肠癌，从分子、细胞、动物、人体水平多个层面进行了深入的研究，发现了肝癌细胞能够感受葡萄糖浓度变化，通过CARM1甲基化GAPDH，降低GAPDH酶活性，继而抑制肝癌细胞的糖酵解和细胞生长；OGDH受极性蛋白Par3调控，酶活性下降，导致肝癌细胞代谢紊乱、线粒体功能异常，从而影响肝癌细胞的恶性生物学行为；CAPS1激活PI3K/Akt/Snail信号通路，调控CRC的转移。项目资助发表了高水平SCI论文4篇，完成了预期研究内容，实现了预期研究目标。研究结果提示CARM1、Par3及CAPS1可能成为肿瘤防治的潜在靶点，CARM1、OGDH及PI3K/Akt通路抑制剂可能成为潜在的肿瘤治疗药物。