Regulation of the Kidney Cancer Epigenome by Oncometabolite L-2-Hydroxyglutarate

肿瘤代谢物 L-2-羟基戊二酸对肾癌表观基因组的调节

• 批准号: 9174385
• 负责人: SUNIL SUDARSHAN
• 金额: $ 37.21万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174385
• 关键词: 14q; Architecture; Biochemical; Brain Neoplasms; Carcinoma; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Data; Development; Disease Management; Enzyme Inhibition; Epigenetic Process; Event; Fumarates; Gene Expression; Genes; Genetic; Genetic Models; Goals; Histones; Hypermethylation; In Vitro; Inborn Errors of Metabolism; Kidney; Knock-out; Knowledge; Laboratories; Lead; Link; Loss of Heterozygosity; Malate Dehydrogenase; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Metastatic Renal Cell Cancer; Methodology; Modeling; Modification; Molecular; Neoplasm Metastasis; Outcome; Oxidoreductase; Pathogenesis; Pathway interactions; Patients; Phenotype; Prevalence; Property; Regulation; Renal Cell Carcinoma; Renal carcinoma; Reporting; Research; Resistance; Role; Succinates; Treatment Efficacy; Woman; Work; advanced disease; base; cancer therapy; carcinogenesis; demethylation; enantiomer; epigenome; genome-wide analysis; improved; improved outcome; in vivo; information gathering; innovation; malignant phenotype; men; methylome; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; research study; small molecule; stable isotope; treatment strategy; tumor; tumor growth; tumor initiation; tumor metabolism; tumor progression; tumorigenesis

PROJECT SUMMARY. Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men and women. Unfortunately, progress in the treatment of patients with advanced disease has been incremental, and new treatment approaches are warranted. Altered metabolism, an established hallmark of malignancy, may provide novel therapeutic opportunities. Oncometabolites, small molecules with putative transforming properties, represent one of the clearest links between metabolism and cancer. A unifying theme amongst the oncometabolites identified to date is their ability to alter the epigenome via inhibition of enzymes involved in DNA and histone demethylation. In the context of RCC, there is increasing recognition of the role of epigenetics to the pathogenesis of this malignancy. However, the drivers of the RCC epigenome remain poorly characterized. The long-term goal of our laboratory is to understand the role of metabolism in renal carcinogenesis to develop novel therapies that will improve outcomes. The objective of this proposal is to identify the metabolic basis for the epigenetic landscape of RCC and to determine the effects on tumorigenesis. Studies by our laboratory and others have identified elevations of the putative oncometabolite (L)-2- hydroxyglutarate (L-2HG) in RCC as well as brain tumors. Elevations of L-2HG in RCC are due to reduced expression of L2HGDH (L-2HG dehydrogenase) which is located on chromosome 14q. Intriguingly, 14q loss is associated with a DNA hypermethylation phenotype, therapy resistance, and worsened outcomes in RCC patients. The central hypothesis of this proposal is that L-2HG is a powerful epigenetic modifier that drives the malignant phenotype of RCC. This hypothesis is based on strong preliminary data demonstrating that re- expression of L2HGDH in RCC cells (and thus lowering of cellular L-2HG levels) can reverse epigenetic modifications and suppresses both in vitro and in vivo tumor phenotypes. Additionally, high L-2HG tumors from patients demonstrate a RCC hypermethylator phenotype. In Aim 1, we will dissect the genetic and biochemical events that lead to L-2HG accumulation. In Aim 2, we will determine the contribution of L-2HG to the hypermethylator phenotype and assess the effects on gene expression utilizing methodologies including next generation sequencing with methylome array. In Aim 3, we will determine the mechanism by which L2HGDH suppresses tumor growth. In addition, we will assess the role of L2HGDH loss in tumor initiation and progression using novel genetic models. The proposed research is significant because it will identify the drivers of the RCC epigenome in the context of targetable pathways. The approach is innovative because it will establish a link between the epigenome and tumor metabolism in RCC. Ultimately, the knowledge gathered has the potential to improve the efficacy of treatment for patients with advanced RCC, an unmet need challenging the contemporary management of this disease.

项目摘要。肾细胞癌（RCC）是两名男性最常见的恶性肿瘤之一 和女人。不幸的是，晚期疾病患者治疗的进展是渐进的， 并有必要采用新的治疗方法。改变的新陈代谢是恶性的既定标志， 可能会提供新颖的治疗机会。 oncometabolites，带有推定转化的小分子 性质是代谢与癌症之间最明确的联系之一。在 迄今为止确定的oncometabolites是他们通过抑制涉及的酶改变表观基因组的能力 DNA和组蛋白脱甲基化。在RCC的背景下，人们对 对这种恶性肿瘤的发病机理的表观遗传学。但是，RCC表观基因组的驱动因素仍然存在 特征不佳。我们实验室的长期目标是了解代谢在肾脏中的作用 致癌作用以开发出可以改善预后的新疗法。该提议的目的是 确定RCC表观遗传景观的代谢基础，并确定对肿瘤发生的影响。 我们的实验室和其他人的研究确定了推定的oncometabolite（L）-2-的升高 RCC和脑肿瘤中的羟基戊二酸（L-2HG）。 RCC中L-2HG的升高是由于减少 位于14q染色体上的L2HGDH（L-2HG脱氢酶）的表达。有趣的是，14q的损失是 与DNA高甲基化表型，耐药性和RCC的结局恶化相关 患者。该提议的核心假设是L-2HG是一种强大的表观遗传修饰符，可驱动 RCC的恶性表型。该假设基于强大的初步数据，表明重新 L2HGDH在RCC细胞中的表达（因此降低了细胞L-2HG水平）可以逆转表观遗传学 修饰并抑制体外和体内肿瘤表型。此外，高L-2HG肿瘤 从患者出现RCC高甲基表型。在AIM 1中，我们将剖析遗传和 导致L-2HG积累的生化事件。在AIM 2中，我们将确定L-2HG对 高甲基甲基表型并评估了利用包括在内的方法的基因表达的影响 使用甲基团阵列进行下一代测序。在AIM 3中，我们将确定该机制 L2HGDH抑制肿瘤的生长。此外，我们将评估L2HGDH损失在肿瘤起始和 使用新型遗传模型进行进展。拟议的研究很重要，因为它将确定 RCC表观基因组的驱动器在可靶向途径的背景下。这种方法是创新的，因为它 将在RCC中建立表观基因组和肿瘤代谢之间的联系。最终，知识 收集的潜力有可能提高晚期RCC患者的治疗功效，这是未满足的需求 挑战当代对这种疾病的管理。