Mechanisms of Metabolic Gene Mutations in Cancer

描述(申请人提供)：在人类癌症中长期观察到代谢调节的改变，并广泛应用于临床肿瘤检测。最近的两个发现--频繁突变的癌症基因对新陈代谢的直接调节和癌症中代谢酶的突变--重新引起了人们对癌症新陈代谢的兴趣。三个频繁突变的癌症基因，p53，Myc和RAS，已经被发现直接调节参与糖酵解的各种代谢酶的表达。编码四种不同代谢酶的Severn代谢基因在人类癌症中经常发生突变，包括延胡索酸水合酶(FH)、琥珀酸脱氢酶(SDHB、SDHC、SDHD和SDH5)以及异柠檬酸脱氢酶-1和-2(IDH1、IDH2)。针对IDH1和IDH2的肿瘤突变经常发生在胶质瘤和白血病中，并分别导致α-酮戊二酸(a-KG)和2-羟基戊二酸(2-HG)产生活性的丧失和增加。我们的初步研究表明，2-HG作为a-KG拮抗剂与催化部位的同一空间结合，竞争性地抑制依赖a-KG的双加氧酶的活性，包括依赖a-KG的组蛋白去甲基酶和Tet家族的5-甲基胞嘧啶羟基酶。因此，IDH1/2突变导致培养细胞和原发胶质瘤中组蛋白和DNA甲基化的整体改变。我们进一步证明，琥珀酸和富马酸，这两种结构上类似于2-HG的代谢物，在表达肿瘤突变体SOH和FH的细胞中积累，在体内和体外类似地抑制组蛋白去甲基酶。这些初步研究使我们提出了一个新的和统一的a-KG途径，它是这七个代谢基因突变对肿瘤发生的贡献的基础。我们假设多种细胞代谢物可以作为a-KG拮抗剂发挥作用，这些代谢物中的任何一个的异常积累都会竞争性地抑制依赖a-KG的组蛋白去甲基酶和Tet羟基酶，导致它们的活性降低，并改变表观遗传控制和细胞命运。结合两位共同研究人员在胶质瘤领域的独特临床专业知识和癌症生物信息学方面的计算专业知识，我们提出了确定a-KG途径的细胞功能、机制、基因和靶点的三个具体目标。目的1：确定IDH突变在细胞转化中的作用目的2：确定SDH和FH基因突变在肿瘤发生中的机制目的3：阐明a-KG途径的基因和靶点

DESCRIPTION (provided by applicant): Altered metabolic regulation has long been observed in human cancer and broadly used in the clinic for tumor detection. Two recent findings-direct regulation of metabolism by frequently mutated cancer genes and mutations of metabolic enzymes in cancer-have renewed interest in cancer metabolism. Three frequently mutated cancer genes, p53, Myc, and Ras, have been found to directly regulate the expression of various metabolic enzymes involved in glycolysis. Severn metabolic genes encoding for four different metabolic enzymes are frequently mutated in human cancer, including fumarate hydratase (FH), succinate gehygrogenase (SDHB, SDHC, SDHD and SDH5), and isocitrate dehydrogenase-1 and -2 (IDH1, IDH2). Tumor mutations targeting IDH1 and IDH2 occur frequently in gliomas and leukemia and cause simultaneous loss and gain of activities in the production of a-ketoglutarate (a-KG) and 2-hydroxyglutarate (2-HG), respectively. Our preliminary studies demonstrated that 2-HG functions as an a-KG antagonist by binding to the same space in the catalytic site and competitively inhibiting the activity of a-KG-dependent dioxygenases, including both a-KG-dependent histone demethylases and TET family 5-methycytosine hydroxylases. Thus mutation of IDH1/2 leads to global alterations of both histone and DNA methylations in cultured cells and in primary gliomas. We further demonstrate that succinate and fumarate, two metabolites that are structurally similar to 2-HG and are accumulated in cells expressing tumor-derived mutant SOH and FH, similarly inhibit histone demethylases in vivo and in vitro. These preliminary studies have led us to propose a novel and unified a-KG pathway that underlies the contribution to the tumorigenesis by the mutations in these seven metabolic genes. We hypothesize that multiple cellular metabolites can function as a-KG antagonists, and that abnormal accumulation of anyone of these metabolites competitively inhibits a-KG-dependent histone demethylases and TET hydroxylases, leading to their reduced activity and altered epigenetic control and cell fate. Combining the unique clinical expertise in glioma and computational expertise in cancer bioinformatics brought in by two co-investigators, we propose three Specific Aims to determine the cellular function, mechanism, genes and targets of the a-KG pathway. Aim 1: Determine the function of IDH mutations in cell transformation Aim 2: Determine the mechanism of SDH and FH gene mutations in tumorigenesis Aim 3: Elucidate the genes and targets of a-KG pathway