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

项目总结。肾细胞癌(RCC)是两人最常见的10种恶性肿瘤之一 还有女人。不幸的是，晚期疾病患者的治疗进展是渐进的， 新的治疗方法是有必要的。新陈代谢改变，这是恶性肿瘤的一个公认标志， 可能提供新的治疗机会。代谢物，具有转化作用的小分子 属性，代表了新陈代谢和癌症之间最明确的联系之一。一个统一的主题在 到目前为止，已确定的肿瘤代谢物是它们通过抑制参与以下过程的酶改变表观基因组的能力 DNA和组蛋白去甲基化。在农村合作委员会的背景下，人们越来越认识到 表观遗传学对这种恶性肿瘤发病机制的影响。然而，RCC表观基因组的驱动因素仍然存在 特征不佳的。我们实验室的长期目标是了解代谢在肾脏中的作用。 致癌，以开发新的疗法，将改善结果。这项建议的目的是 确定肾细胞癌表观遗传格局的代谢基础，并确定其对肿瘤发生的影响。 我们实验室和其他人的研究已经确定了推定的钉螺代谢物(L)-2-的海拔- 羟基戊二酸(L-2HG)在肾癌和脑肿瘤中的表达。L-2HG在碾压混凝土中的海拔高度因降低而降低 位于14Q染色体上的L脱氢酶基因的表达。耐人寻味的是，14Q亏损 与肾癌的DNA高甲基化表型、治疗耐药和预后恶化相关 病人。这一提议的中心假设是，L-2HG是一种强大的表观遗传学修饰物，推动 肾癌的恶性表型。这一假说是基于强有力的初步数据，该数据表明， L2HGDH在肾癌细胞中的表达(从而降低细胞内L-2HG水平)可以逆转表观遗传学 修饰和抑制体外和体内的肿瘤表型。此外，高L-2HG肿瘤 患者表现为肾癌高甲基化表型。在目标1中，我们将剖析基因和 导致L-2HG蓄积的生化事件。在目标2中，我们将确定L-2HG对 超甲基化子的表型和评估对基因表达的影响的方法包括 利用甲基组阵列进行下一代测序。在目标3中，我们将确定 L2HGDH抑制肿瘤生长。此外，我们还将评估L2HGDH缺失在肿瘤发生和发展中的作用。 使用新的遗传模型的进展。拟议的研究具有重要意义，因为它将确定 靶向通路背景下RCC表观基因组的驱动因素。这种方法是创新的，因为它 将在肾癌的表观基因组和肿瘤代谢之间建立联系。归根结底，知识 Aggreged有可能提高晚期肾癌患者的治疗效果，这是一种尚未得到满足的需求 对这种疾病的当代管理提出挑战。

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.