Interaction between the Epitranscriptome and Metabolism in L-2HG Driven Kidney Cancer

L-2HG 驱动的肾癌中表观转录组与代谢之间的相互作用

• 批准号: 10680472
• 负责人: SUNIL SUDARSHAN
• 金额: $ 36.38万
• 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: 2016-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680472
• 关键词: Anabolism; Automobile Driving; Biological; Biology; Cancer Patient; Data; Development; Enzymes; Face; Gene Expression; Genes; Glucose; Glycolysis; Goals; Growth; High Prevalence; Human; Hypermethylation; Kidney; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Methodology; Methylation; Methyltransferase; Modeling; Modification; Molecular; Neoplasm Metastasis; Nucleotides; Oncogenic; Outcome; PF4 Gene; Pathway interactions; Patients; Phenotype; Prognosis; RNA; RNA methylation; Renal Cell Carcinoma; Renal carcinoma; Reporting; Role; Serine; Time; Transgenic Model; Translations; Tumor Biology; Tumor Promotion; Woman; Work; advanced disease; amino acid metabolism; aminoacid biosynthesis; cancer cell; cancer therapy; deprivation; dietary; epitranscriptome; epitranscriptomics; experimental study; glucose metabolism; in vivo; innovation; mRNA Stability; men; methylome; multidisciplinary; neoplastic cell; novel; novel strategies; novel therapeutic intervention; patient derived xenograft model; pharmacologic; ribosome profiling; small molecule; transcription factor; transcriptomics; tumor; tumor growth; tumor metabolism

PROJECT SUMMARY. Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men and women. Although outcomes are excellent for patients with tumors confined to the kidney, patients with advanced disease face unfavorable outcomes despite several approved therapies. This underscores the need for new treatment strategies. We have identified elevations of the oncometabolite L-2-hydroxyglutarate (L-2HG) in a significant proportion of RCCs. Oncometabolites are small molecules that aberrantly accumulate in cancer cells and can impact tumors in many ways. Our studies reveal that L-2HG is a potent driver of RCC growth leading us to investigate the mechanisms by which this small molecule exerts its oncogenic activity. Delineating these effects will inform novel strategies for oncometabolite-driven kidney cancer. Our preliminary studies have uncovered two novel findings. First, L-2HG is a powerful regulator of the epitranscriptome. In particular, our preliminary studies demonstrate that L-2HG promotes accumulation of the RNA mark, N6-methyladenosine (m6A). m6A is the most prevalent nucleotide modification in eukaryotic mRNA and can profoundly impact gene expression (e.g. mRNA stability, translation). Second, L-2HG remodels tumor metabolism. Our compelling preliminary data indicate that these two findings are intricately linked leading us to propose the innovative hypothesis that L-2HG induced RNA hypermethylation remodels metabolism to drive tumor growth but creates metabolic liabilities. In Aim 1 we will determine the molecular underpinning by which L-2HG promotes RNA methylation and the functional significance of this effect. In Aim 2, we will dissect the mechanisms by which L- 2HG remodels metabolism with specific focus on glucose utilization and its support of anabolic activities. In Aim 3, we will assess the impact of L-2HG induced metabolic remodeling on tumor growth. In addition, we will determine if this remodeling creates metabolic vulnerabilities. Leveraging our expertise in the field, we will incorporate novel models generated by our group and apply state of the art methodologies such as ribosome profiling to study the biology of L-2HG. The proposal work is significant as it will likely lead to novel approaches that target either the epitranscriptome and/or tumor metabolism. The proposal is timely given recent proof-of- principle studies demonstrating that these approaches are pharmacologically targetable. We have assembled a multidisciplinary team required for the successful completion of the proposed studies. Given the prevalence of high L-2HG RCC, we are poised to advance the field with findings that will impact a significant proportion of kidney cancer patients.

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。尽管结局非常适合限制于肾脏的肿瘤患者，但患者 尽管经过多种疗法，晚期疾病仍会面临不利的结果。这突显了需求 用于新的治疗策略。我们已经确定了oncometabolite L-2-羟基戊二酸（L-2HG）的高程 RCC的很大比例。 oncometabolites是在癌症中异常积累的小分子 细胞并可以在许多方面影响肿瘤。我们的研究表明，L-2HG是RCC增长的有效驱动力 导致我们研究该小分子发挥其致癌活性的机制。描绘 这些效果将为康代谢物驱动的肾脏癌的新型策略提供信息。我们的初步研究 发现了两个新颖的发现。首先，L-2HG是表面翻译组的强大调节器。特别是我们的 初步研究表明，L-2HG促进RNA标记的积累N6-甲基读腺苷 （M6A）。 M6a是真核mRNA中最普遍的核苷酸修饰，可以深刻影响基因 表达（例如mRNA稳定性，翻译）。其次，L-2HG重塑肿瘤代谢。我们引人注目的 初步数据表明，这两个发现复杂地联系在一起，导致我们提出了创新 假设L-2HG诱导RNA高甲基化重塑代谢可驱动肿瘤生长，但会产生 代谢负债。在AIM 1中，我们将确定L-2HG促进RNA的分子基础 甲基化和该作用的功能意义。在AIM 2中，我们将剖析l-的机制 2HG重塑新陈代谢，特别关注葡萄糖利用及其对合成代谢活性的支持。目标 3，我们将评估L-2HG诱导的代谢重塑对肿瘤生长的影响。此外，我们将 确定此重塑是否会产生代谢漏洞。利用我们在该领域的专业知识，我们将 合并我们的小组生成的新颖模型并应用艺术方法（例如核糖体） 分析研究L-2HG的生物学。提案工作很重要，因为它可能会导致新颖的方法 该靶向表面参考组和/或肿瘤代谢。鉴于最近的证明，该提议是及时的 原则研究表明，这些方法在药理学上是可定位的。我们已经组装了 一个多学科团队需要成功完成拟议的研究。考虑到患病率 在高L-2HG RCC中，我们有望通过发现会影响很大比例的发现来推进该领域 肾癌患者。