HDAC7-driven metabolic remodeling in renal tumor progression

肾细胞癌(RCC)是男性和女性最常见的10种恶性肿瘤之一。它也是一种 在退伍军人中普遍存在的恶性肿瘤。退伍军人事务部癌症登记中心(VACCR)分析 数据显示，肾癌是退伍军人中最常见的癌症之一。这个 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。三分之一的患者会发展成 转移。不幸的是，大多数发生转移的患者会死于他们的疾病。这些现实 造成了两个根本的差距：1)在RCC中调解攻击行为的机制是什么？ 2)我们能针对这些机制吗？这项提案的目标将是解决这些主要差距 实地改善退伍军人以及更多受RCC困扰的人口的结果。肾是其中之一 人体新陈代谢最活跃的器官。值得注意的是，RCC的代谢发生了戏剧性的变化 基因表达程序。肾细胞癌中研究最深入的代谢途径是糖酵解。 由于缺氧诱导因子的表达增加，介导这一途径的一些酶的表达上调 (HIF)。然而，同样令人信服的表型是我们的数据显示显著减少的表达 调节支链氨基酸(BCAA)分解代谢(即分解)的酶。BCAA是 必需的氨基酸，因此必须从饮食中获得。支链氨基酸的分解代谢发生在 线粒体，由一系列复杂的反应组成，这些反应介导了缬氨酸、亮氨酸和 异亮氨酸。在所有类型的肿瘤中，支链氨基酸分解代谢程序的缺失与 肾癌患者的死亡。尽管有这种令人信服的联系，但推动这种重塑的机制 它对肿瘤生物学的影响还知之甚少。这项建议的目标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 去乙酰酶7(HDAC7)抑制肾细胞癌支链氨基酸分解代谢基因表达的研究我们的数据显示 这基于我们的发现表明HDAC7抑制作用将支链氨基酸转向促癌途径 恢复支链氨基酸分解代谢酶的表达，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了新的假设，即HDAC7重新编程支链氨基酸代谢 推动RCC进展这一中心假设，基于强大的初步数据，将通过追踪进行检验 1)确定支链氨基酸分解代谢被抑制的表观遗传学基础 肾癌，2)确定支链氨基酸分解代谢受抑在肾癌发生中的作用，以及3)确定 支链氨基酸在促进肿瘤侵袭性行为中的新信号作用。我们将描述饮食是如何 表观基因组，与代谢相互作用，激活下游信号事件，对肾脏肿瘤的生长和 进步。通过剖析这些分子机制并展示它们的重要性，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预后。

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.