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 10 种最常见的恶性肿瘤之一。它也是一个 退伍军人中普遍存在的恶性肿瘤。 VA 中心癌症登记处 (VACCR) 分析 数据表明，肾癌是退伍军人中最常见的癌症之一。这 最常见的组织学是透明细胞肾细胞癌 (ccRCC)，这是本提案的重点。三分之一的患者会出现 转移。不幸的是，大多数发生转移的患者将死于该病。这些现实 造成了两个根本性的差距：1）介导 RCC 攻击行为的机制是什么？ 2）我们可以针对这些机制吗？该提案的目标是解决这些主要差距 领域，以改善退伍军人以及更多患有 RCC 的人群的结果。肾脏位于其中 人体代谢最活跃的器官。值得注意的是，肾细胞癌的代谢发生了巨大的变化 基因表达程序。 RCC 中研究最充分的代谢途径是糖酵解，其表达如下： 由于缺氧诱导因子表达增加，介导该途径的酶上调 （高频）。然而，一个同样引人注目的表型是我们的数据表明， 介导支链氨基酸 (BCAA) 分解代谢（即分解）的酶。支链氨基酸是 必需氨基酸，因此必须从饮食中获取。 BCAA 分解代谢发生在 线粒体由一系列复杂的反应组成，介导缬氨酸、亮氨酸和 异亮氨酸。在所有肿瘤类型中，支链氨基酸分解代谢程序的丧失与以下因素密切相关： 肾癌患者的死亡。尽管存在这种引人注目的联系，但推动这种重塑的机制 及其对肿瘤生物学的影响知之甚少。该提案的目的是确定关键驱动因素 代谢重塑以及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，这将 改善患者的治疗效果。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) 抑制 RCC 中 BCAA 分解代谢基因表达程序。我们的数据表明 根据我们的研究结果，这将 BCAA 重新路由至促肿瘤发生途径，证明 HDAC7 抑制 恢复 BCAA 分解代谢酶的表达并抑制体内肿瘤生长。反过来，我们的数据 发现支链氨基酸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新的假设：HDAC7 重编程支链氨基酸代谢 推动 RCC 进展 这一中心假设基于强有力的初步数据，将通过追求进行检验 以下具体目标：1) 确定 BCAA 分解代谢被抑制的表观遗传基础 肾癌，2) 确定受抑制的 BCAA 分解代谢在肾癌发生中的作用，以及 3) 确定 BCAA 的新信号传导作用可促进肿瘤侵袭行为。我们将描述饮食如何 表观基因组和代谢相互作用，激活对肾肿瘤生长至关重要的下游信号事件 进展。通过剖析这些分子机制并证明它们的重要性，我们期望 确定新的干预机会，以改善受肾癌影响的退伍军人的治疗结果。