HDAC7-driven metabolic remodeling in renal tumor progression

HDAC7 驱动的肾肿瘤进展中的代谢重塑

• 批准号: 10587999
• 负责人: SUNIL SUDARSHAN
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587999
• 关键词: Acceleration; Address; Aggressive behavior; Amino Acids; Behavior; Biological; Branched-Chain Amino Acids; Catabolism; Cessation of life; Clear cell renal cell carcinoma; Clinic; Common Neoplasm; Complex; Data; Diet; Disease; Enzymes; Epigenetic Process; Essential Amino Acids; Event; Gene Expression; Genes; Glycolysis; Goals; Growth; Histology; Histone Deacetylase; Histone Deacetylase Inhibitor; Human body; Hypoxia Inducible Factor; Intervention; Invaded; Isoleucine; Kidney; Kidney Neoplasms; Leucine; Link; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Neoplasm Metastasis; Organ; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Population; Proliferating; Proteins; Reaction; Renal Cell Carcinoma; Renal carcinoma; Role; Route; Sampling; Series; Signal Transduction; Stable Isotope Labeling; Testing; Therapeutic; Translating; Tumor Biology; Valine; Veterans; Woman; Work; Xenograft Model; amino acid metabolism; cancer cell; carcinogenesis; chromatin remodeling; data registry; dietary; epigenome; genome-wide; improved; improved outcome; in vivo; innovation; insight; men; metabolic abnormality assessment; metabolomics; migration; military veteran; neoplasm registry; neoplastic cell; novel; novel strategies; patient derived xenograft model; patient prognosis; pharmacologic; programs; promoter; rapid growth; tumor; tumor behavior; tumor growth; tumor metabolism; tumor progression

Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men and women. It is also a malignancy that is prevalent in the Veteran population. An analysis of VA Central Cancer Registry (VACCR) data demonstrates that cancer of the kidney is among the most common cancers in the veteran population. The most common histology is clear cell RCC (ccRCC), the focus of this proposal. One-third of patients will develop metastasis. Unfortunately, most patients who develop metastasis will die from their disease. These realities have created two fundamental gaps: 1) what are the mechanisms that mediate aggressive behavior in RCC? and 2) can we target these mechanisms? The goals of this proposal will be to address these major gaps in the field to improve outcome for Veterans, as well as the greater population afflicted with RCC. The kidney is among the most metabolically active organs in the human body. Notably, RCC harbors dramatic alterations in metabolic gene expression programs. The most well-studied metabolic pathway in RCC is glycolysis as the expression of enzymes that mediate this pathway are upregulated due increased expression of hypoxia inducible factor (HIF). However, an equally compelling phenotype is our data demonstrating dramatically reduced expression of enzymes that mediate the catabolism (i.e., breakdown) of branched chain amino acids (BCAAs). BCAAs are essential amino acids, and therefore must be obtained from the diet. BCAA catabolism occurs in the mitochondria and consists of a complex series of reactions that mediate the breakdown of valine, leucine, and isoleucine. Amongst all tumor types, loss of the BCAA catabolism program is most strongly associated with death for patients with kidney cancer. Despite this compelling link, the mechanisms that drive this remodeling and its impact on tumor biology are poorly understood. The objective of this proposal is to identify the key drivers of metabolic remodeling and the molecular underpinnings by which this remodeling propels tumor progression. Elucidating this molecular connection will yield novel strategies to counter tumor progression which would improve patient outcomes. Our preliminary data uncover a novel role for the epigenetic factor histone deacetylase 7 (HDAC7) in suppressing the BCAA catabolic gene expression program in RCC. Our data indicate this reroutes BCAAs toward protumorigenic pathways based on our findings demonstrating that HDAC7 inhibition restores expression of BCAA catabolism enzymes and suppresses tumor growth in vivo. In turn, our data uncover a novel role for BCAAs in the activation of signaling nodes that promote aggressive behaviors in cancer cells. These data have led us to propose the novel hypothesis that HDAC7 reprogramming of BCAA metabolism drives RCC progression This central hypothesis, based on strong preliminary data, will be tested through pursuit of the following specific aims: 1) determine the epigenetic basis by which BCAA catabolism is suppressed in kidney cancer, 2) determine the role of suppressed BCAA catabolism in renal carcinogenesis, and 3) determine novel signaling roles for BCAAs that promote aggressive tumor behavior. We will delineate how diet, the epigenome, and metabolism interact to activate downstream signaling events critical to renal tumor growth and progression. By dissecting these molecular mechanisms and demonstrating their significance, we expect to identify novel opportunities for intervention to improve outcomes for veterans impacted by kidney cancer.

肾细胞癌（RCC）是男性和女性中最常见的10种恶性肿瘤之一。也是一 在退伍军人群体中普遍存在的恶性肿瘤。VA中央癌症登记（VACCR）分析 数据显示，肾癌是退伍军人群体中最常见的癌症之一。的 最常见的组织学是透明细胞RCC（ccRCC），这是本提案的重点。三分之一的患者会发展成 转移不幸的是，大多数发生转移的患者将死于他们的疾病。这些现实 造成了两个基本的差距：1）什么是介导RCC攻击行为的机制？ （2）我们是否可以针对这些机制？本提案的目标是解决这些主要差距， 领域，以改善退伍军人的结果，以及更多的人口与RCC折磨。肾脏是 人体内代谢最活跃的器官值得注意的是，肾细胞癌具有显著的代谢改变， 基因表达程序。肾细胞癌中研究最多的代谢途径是糖酵解， 由于缺氧诱导因子表达增加，介导该途径的酶上调 （HIF）。然而，一个同样引人注目的表型是我们的数据表明， 介导催化剂的酶（即，支链氨基酸（BCAA）的分解。BCAA是 必需氨基酸，因此必须从饮食中获得。BCAA催化剂发生在 线粒体并由一系列复杂的反应组成，这些反应介导缬氨酸、亮氨酸和脯氨酸的分解。 异亮氨酸在所有肿瘤类型中，BCAA catalysts程序的丢失与以下因素最密切相关： 肾癌患者的死亡率。尽管有这种令人信服的联系，驱动这种重塑的机制 及其对肿瘤生物学的影响知之甚少。本提案的目的是确定关键驱动因素 代谢重塑和这种重塑推动肿瘤进展的分子基础。 阐明这种分子联系将产生对抗肿瘤进展的新策略， 改善患者预后。我们的初步数据揭示了表观遗传因子组蛋白的新作用 脱乙酰酶7（HDAC7）在抑制RCC中BCAA分解代谢基因表达程序中的作用。我们的数据表明 基于我们的发现，这将BCAA重新导向促肿瘤途径，表明HDAC7抑制 恢复BCAA催化酶的表达并抑制体内肿瘤生长。反过来，我们的数据 发现BCAA在激活促进癌症侵袭行为的信号节点中的新作用 细胞这些数据使我们提出了新的假设，即BCAA代谢的HDAC7重编程 这一中心假设基于强有力的初步数据，将通过追踪来检验。 以下具体目标：1）确定BCAA catalysts被抑制的表观遗传基础， 肾癌，2）确定抑制的BCAA催化剂在肾癌发生中的作用，和3）确定 BCAA的新信号作用，促进肿瘤的侵袭行为。我们将描述如何饮食， 表观基因组和代谢相互作用以激活对肾肿瘤生长至关重要的下游信号传导事件， 进展通过剖析这些分子机制并证明其重要性，我们希望 确定新的干预机会，以改善受肾癌影响的退伍军人的预后。