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) 是男性中 10 种最常见的恶性肿瘤之一 和妇女。尽管肿瘤局限于肾脏的患者预后良好，但患有以下疾病的患者 尽管有几种已获批准的疗法，但晚期疾病仍面临不利的结果。这强调了需要 寻求新的治疗策略。我们已经确定致癌代谢物 L-2-羟基戊二酸 (L-2HG) 升高 在相当大比例的农村信用社中。肿瘤代谢物是在癌症中异常积累的小分子 细胞并可以通过多种方式影响肿瘤。我们的研究表明 L-2HG 是 RCC 生长的强大驱动力 引导我们研究这种小分子发挥致癌活性的机制。描绘 这些效应将为治疗肿瘤代谢物驱动的肾癌提供新的策略。我们的初步研究有 发现了两项新发现。首先，L-2HG 是表观转录组的强大调节剂。特别是，我们的 初步研究表明 L-2HG 促进 RNA 标记 N6-甲基腺苷的积累 (m6A)。 m6A 是真核生物 mRNA 中最常见的核苷酸修饰，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，这两项发现错综复杂，促使我们提出创新方案 假设 L-2HG 诱导 RNA 高甲基化重塑代谢以驱动肿瘤生长，但会产生 代谢负债。在目标 1 中，我们将确定 L-2HG 促进 RNA 的分子基础 甲基化以及这种效应的功能意义。在目标 2 中，我们将剖析 L- 2HG 重塑新陈代谢，特别关注葡萄糖利用及其对合成代谢活动的支持。瞄准 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 确定这种重塑是否会造成代谢脆弱性。凭借我们在该领域的专业知识，我们将 结合我们小组生成的新颖模型并应用最先进的方法，例如核糖体 分析以研究 L-2HG 的生物学。该提案的工作意义重大，因为它可能会带来新的方法 靶向表观转录组和/或肿瘤代谢。鉴于最近的证据，该提案是及时的—— 原理研究表明这些方法在药理学上是可靶向的。我们已经集合了 成功完成拟议研究需要一个多学科团队。鉴于流行程度 对于高 L-2HG RCC，我们准备通过将影响很大一部分的研究结果来推进该领域的发展 肾癌患者。