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: 9307758
• 负责人: SUNIL SUDARSHAN
• 金额: $ 36.07万
• 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/9307758
• 关键词: 14q; Architecture; Biochemical; Brain Neoplasms; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Data; Development; Disease Management; Enzyme Inhibition; Epigenetic Process; Event; Fumarates; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Goals; Histones; Hypermethylation; In Vitro; Inborn Errors of Metabolism; Kidney; Knock-out; Knowledge; Laboratories; Lead; Link; Loss of Heterozygosity; Malate Dehydrogenase; Malignant Epithelial Cell; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Metastatic Renal Cell Cancer; Methodology; Modeling; Modification; Molecular; Neoplasm Metastasis; Outcome; Oxidoreductase; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Prevalence; Property; Regulation; Renal Cell Carcinoma; Renal carcinoma; Reporting; Research; Resistance; Role; Succinates; Treatment Efficacy; Woman; advanced disease; base; cancer therapy; carcinogenesis; demethylation; enantiomer; epigenome; experimental study; genome-wide analysis; improved; improved outcome; in vivo; innovation; malignant phenotype; men; methylome; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; 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) 是男性中 10 种最常见的恶性肿瘤之一 和妇女。不幸的是，晚期疾病患者的治疗进展一直在渐进， 新的治疗方法是必要的。新陈代谢改变是恶性肿瘤的一个既定标志， 可能提供新的治疗机会。肿瘤代谢物，具有推定转化作用的小分子 特性，代表了代谢与癌症之间最明显的联系之一。一个统一的主题 迄今为止发现的致癌代谢物是通过抑制参与的酶来改变表观基因组的能力 DNA 和组蛋白去甲基化。在 RCC 背景下，人们越来越认识到 这种恶性肿瘤发病机制的表观遗传学。然而，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 致癌作用以开发可改善结果的新疗法。该提案的目的是 确定 RCC 表观遗传景观的代谢基础并确定其对肿瘤发生的影响。 我们的实验室和其他实验室的研究已经确定了假定的致癌代谢物 (L)-2- 的升高 羟基戊二酸 (L-2HG) 在肾细胞癌和脑肿瘤中的作用。 RCC 中 L-2HG 的升高是由于减少 位于染色体 14q 上的 L2HGDH（L-2HG 脱氢酶）的表达。有趣的是，14q 损失是 与 RCC 的 DNA 高甲基化表型、治疗耐药和预后恶化相关 患者。该提案的中心假设是 L-2HG 是一种强大的表观遗传修饰剂，可驱动 RCC 的恶性表型。该假设基于强有力的初步数据，表明重新 RCC 细胞中 L2HGDH 的表达（从而降低细胞 L-2HG 水平）可以逆转表观遗传 修饰和抑制体外和体内肿瘤表型。此外，高 L-2HG 肿瘤 来自患者的研究显示出 RCC 高甲基化表型。在目标 1 中，我们将剖析遗传和 导致 L-2HG 积累的生化事件。在目标 2 中，我们将确定 L-2HG 对 超甲基化表型并利用方法评估对基因表达的影响，包括 使用甲基化组阵列进行下一代测序。在目标 3 中，我们将确定机制 L2HGDH 抑制肿瘤生长。此外，我们将评估 L2HGDH 缺失在肿瘤发生和发生中的作用。 使用新颖的遗传模型进行进展。拟议的研究意义重大，因为它将确定 靶向途径背景下 RCC 表观基因组的驱动因素。该方法具有创新性，因为它 将在 RCC 的表观基因组和肿瘤代谢之间建立联系。最终，知识 聚集的药物有可能提高晚期肾细胞癌患者的治疗效果，这是一项未得到满足的需求 对这种疾病的当代治疗提出了挑战。