Mechanisms of Metabolic Gene Mutations in Cancer

癌症代谢基因突变的机制

• 批准号: 8219796
• 负责人: YUE XIONG
• 金额: $ 35.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8219796
• 关键词: Acute Myelocytic Leukemia; Binding; Bioinformatics; Cancer Gene Mutation; Catalytic Domain; Cell Fate Control; Cell physiology; Cells; Clinic; Clinical; Cultured Cells; DNA Methylation; Data; Detection; Development; Dioxygenases; Enzymes; Epigenetic Process; Family; Fumarate Hydratase; Fumarates; Gene Mutation; Gene Targeting; Genes; Glioblastoma; Glioma; Glycolysis; Hereditary Paraganglioma; Histones; Human; Human Development; In Vitro; Isocitrate Dehydrogenase; Malignant Neoplasms; Metabolic; Metabolism; Mixed Function Oxygenases; Mutate; Mutation; Oncogenes; Pathway interactions; Production; Regulation; Renal Cell Carcinoma; Research; Research Personnel; Sampling; Stem cells; Succinate Dehydrogenase; Succinates; Tumor-Derived; Uterine Fibroids; alpha ketoglutarate; cell transformation; enzyme activity; exome; in vivo; interest; leukemia; mutant; novel; relating to nervous system; self-renewal; stem; tumor; tumorigenesis

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 PUBLIC HEALTH RELEVANCE: This proposal seeks to understand how mutation of metabolic genes contributes to the development of human cancer. Specifically, we will examine how mutations in isocitrate dehydrogenase, which are found in about 20% of acute myeloid leukemias and more than 75% secondary glioblastomas, promote tumor formation. We will investigate the possibility that additional cancer-associated mutations in metabolic enzymes, including succinate dehydrogenase (mutated in familial paraganglioma) and fumarate hydratase (mutated in renal cell carcinoma and uterine leiomyomata), contribute to cancer development in a similar fashion. Accomplishment of these research objectives will have a direct and broad impact on the field of metabolism and cancer.

描述（由申请人提供）：长期以来在人类癌症中观察到代谢调节的改变，并广泛用于临床肿瘤检测。最近的两项发现——频繁突变的癌症基因对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代谢的兴趣。三种经常突变的癌症基因：p53、Myc 和 Ras，已被发现可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七种代谢基因在人类癌症中经常发生突变，包括富马酸水合酶（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神经胶质瘤和白血病中，并分别导致 α-酮戊二酸 (a-KG) 和 2-羟基戊二酸 (2-HG) 生产活性同时丧失和增强。我们的初步研究表明，2-HG 通过与催化位点的相同空间结合并竞争性抑制 a-KG 依赖性双加氧酶（包括 a-KG 依赖性组蛋白去甲基酶和 TET 家族 5-甲基胞嘧啶羟化酶）的活性，发挥 a-KG 拮抗剂的作用。因此，IDH1/2 的突变导致培养细胞和原发性神经胶质瘤中组蛋白和 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与 2-HG 相似的代谢物在表达肿瘤衍生突变体 SOH 和 FH 的细胞中积累，在体内和体外同样抑制组蛋白去甲基酶。 这些初步研究使我们提出了一种新颖且统一的 a-KG 途径，该途径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充当 a-KG 拮抗剂，并且这些代谢物中任何一种的异常积累都会竞争性抑制 a-KG 依赖性组蛋白去甲基化酶和 TET 羟化酶，导致其活性降低并改变表观遗传控制和细胞命运。结合两位共同研究者在神经胶质瘤方面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，我们提出了三个具体目标来确定 a-KG 通路的细胞功能、机制、基因和靶标。 目标 1：确定 IDH 突变在细胞转化中的功能 目标 2：确定 SDH 和 FH 基因突变在肿瘤发生中的机制 目标 3：阐明 a-KG 通路的基因和靶标 公共健康相关性：该提案旨在了解代谢基因突变如何促进人类癌症的发展。具体来说，我们将研究异柠檬酸脱氢酶的突变如何促进肿瘤形成，异柠檬酸脱氢酶存在于约 20% 的急性髓系白血病和超过 75% 的继发性胶质母细胞瘤中。我们将研究代谢酶中与癌症相关的其他突变，包括琥珀酸脱氢酶（在家族性副神经节瘤中突变）和富马酸水合酶（在肾细胞癌和子宫肌瘤中突变）以类似的方式促进癌症发展的可能性。这些研究目标的实现将对代谢和癌症领域产生直接而广泛的影响。