IDH突变促进肿瘤干细胞形成及间充质细胞转化的分子机理

Metabolic enzyme isocitrate fehydrogenase 1(IDH11) mutations are found in several types of cancers including glioma and leukimia. However, molecular mechanism that underline tumorigenesis of IDH1 mutations remain not perfectly elucidated. IDH1 mutation lead to loss and gain of activities in the production of a-ketoglutarate (aKG) and 2-hydroxyglutarate (2HG), respectively. We demonstrated that 2-HG is a competitive inhibitor of multiple a-KG-dependent dioxygenases including prolyl hydroxylase , the families of histone demethylases and TET 5-methylcytosine hydroxylases. Inhibition of a-KG-dependent PHD2 and other dioxygenases leads to changing the expression of large number of genes, among them are epithelial-mesenchymal transitions (EMT) markers and stem cell induction factors. Given that Tumor-derived mutations in IDH1 have been reported to occur at a very early stage during glioma and leukemia development, we hypothesis that IDH1 mutations may contribute to tumorigenesis through activating tumor stem cell formation and epithelial-mesenchymal transitions.In this study,we will moniter the changes of stem cell inducing factors as well as epithelial-mesenchymal transition markers under different aKG and 2HG concentrations, achieved by supplementation, overexpression IDH11 mutant or gene silencing techniques.These studies will provide links between aKG and 2HG variations and EMT or cancer stem cell generation. Our study will provide in deepth mechanism underlying IDH11 mutation tumrigenesis and add value to dieases control.

在系列肿瘤中高频率发生的异柠檬酸脱氢酶1（IDH1）突变致癌机制未完全阐明。我们及同行的研究表明：IDH1突变导致的代谢物失衡，如2HG的累积和aKG浓度的降低，抑制了以aKG为底物的系列双加氧酶催化活性，进而导致细胞表观遗传及HIF等信号通路的改变。本课题计划深入研究IDH1突变引起的表观遗传及信号通路改变促肿瘤的具体机制。基于系列表皮-间质转化因子（EMT）及肿瘤干细胞（CSC）诱导因子是HIF信号通路以及组蛋白甲基化下游靶标基因的事实，我们认为IDH1突变可以促进EMT发生和CSC形成。我们将在培养细胞系中，通过各种研究方法改变细胞中2HG及aKG的浓度，检测EMT及CSC标志物随着2HG及aKG改变的变化规律,明确2HG累积及aKG减少对于EMT及CSC的促进作用。前期结果支持这一假说。项目的成功实施将为代谢失调导致肿瘤的分子机理提供重要线索。

在前期研究结果的基础上，我们的研究表明：肿瘤相关的代谢酶IDH、FH、SDH突变会通过抑制SDH活性导致蛋白质赖氨酸高琥珀酰化修饰，进而抑制细胞的线粒体活性并诱导细胞对凋亡的抵抗，使细胞具有肿瘤表型。我们的研究从全新的角度诠释了代谢物相关蛋白翻译后修饰与线粒体功能调控之间的关系；首次报道代谢物2HG失调直接导致代谢重编程，诱导肿瘤表型。这部分研究结果于2015年发表在molecular杂志上，论文发表后迅速被美国癌症协会旗下最好刊物Cancer Discovery专文介绍。.这部分研究结果从全新的角度诠释了代谢物相关蛋白翻译后修饰与线粒体功能调控之间的关系，也为关于线粒体功能干预、调控方面的研究提供了其他的可能方向。