Studying metabolic stress signaling in renal cancer

项目摘要 肾细胞癌(RCC)是一种主要的代谢性癌症，几个众所周知的肾癌基因是 参与对新陈代谢压力做出反应的途径。因此，迫切需要了解新陈代谢。 参与肾癌发展的应激途径，并开发针对基础代谢的治疗方法 RCC中的漏洞。BAP1在肾细胞癌中作为肿瘤抑制基因，失活突变高达15% Clear cell RCC(CcRCC)和BAP1突变的ccRCC患者的病例数和频繁缺失 尤其是临床结果很差。然而，BAP1在肾癌中是如何发挥肿瘤抑制作用的仍然存在。 目前还不清楚，目前还没有有效的治疗方法来治疗带有BAP1突变的肾癌患者。BAP1及其ITS 相关蛋白形成多梳抑制脱泛素酶(PR-DUB)复合体，它能减少组蛋白2A 染色质上的泛素化(H_2Aub)并调节基因转录。SLC7A11是一种胱氨酸转运蛋白。我们的 最近的出版物和初步数据将BAP1与SLC7A11联系起来，并支持我们的 提出：(1)含BAP1的PR-DUB复合体介导H_2Aub脱泛素和转录 抑制SLC7A11，以及PR-DUB复合体中BAP1缺失或其他成分的改变 抑制SLC7A11的表达，使肾癌细胞对铁下垂(一种非凋亡性细胞)更具抵抗力 代谢应激导致的死亡)并促进肾细胞癌的发展；和(Ii)BAP1缺陷/突变肾脏 肿瘤的生存更依赖于葡萄糖，部分原因是这些肿瘤中SLC7A11的高表达， 从而暴露出新陈代谢的脆弱性，用于治疗靶向。在这项建议中，我们将采用多学科 检验我们假设的方法。提出这项研究的理由是，研究 BAP1-SLC7A11信号轴在铁性下垂和糖依赖中的作用 肾癌细胞如何绕过铁链细胞死亡而存活和生长，但也提供了重要的见解 开发新的治疗策略，以针对肾癌伴发的代谢脆弱性。 就预期结果而言，我们建议的研究将确定铁性下垂的新调节机制。 途径，阐明BAP1的肿瘤抑制功能，并寻找针对新陈代谢的新的有效治疗方法 肾癌的脆弱性。我们的提案具有很高的创新性，因为它侧重于以前未探索过的 将代谢应激信号与肿瘤发展和治疗联系起来的途径。我们提议的研究将会有 对我们理解代谢应激反应的基本机制和 我们在肾癌治疗中针对营养依赖的能力。

Project Summary Renal cell carcinoma (RCC) is a major metabolic cancer, and several well-known renal cancer genes are involved in pathways that respond to metabolic stress. Thus, there is a critical need to understand the metabolic stress pathways involved in RCC development and to develop treatments that target the fundamental metabolic vulnerabilities in RCC. BAP1 acts as a tumor suppressor gene in RCC, with inactivating mutations in up to 15% of cases and frequent deletion in clear cell RCCs (ccRCCs), and patients with BAP1-mutant ccRCC exhibit particularly poor clinical outcomes. However, how BAP1 functions as a tumor suppressor in renal cancer remains unclear, and currently there is no effective therapy to treat RCC patients with BAP1 mutations. BAP1 and its associated proteins form the polycomb repressive deubiquitinase (PR-DUB) complex, which reduces histone 2A ubiquitination (H2Aub) on chromatin and regulates gene transcription. SLC7A11 is a cystine transporter. Our recent publications and preliminary data link BAP1 to SLC7A11 and support the central hypotheses of our proposal that (i) the BAP1-containing PR-DUB complex mediates H2Aub de-ubiquitination and transcriptional repression of SLC7A11, and BAP1 deficiency or alteration of other components in the PR-DUB complex de- represses SLC7A11 expression, rendering renal cancer cells more resistant to ferroptosis (a non-apoptotic cell death induced by metabolic stress) and contributing to RCC development; and (ii) BAP1-deficient/mutant renal tumors are more dependent on glucose for survival, partly due to high SLC7A11 expression in these tumors, thus exposing a metabolic vulnerability for therapeutic targeting. In this proposal, we will employ multi-disciplinary approaches to test our hypotheses. The rationale for the proposed research is that studying the roles of the BAP1-SLC7A11 signaling axis in ferroptosis and glucose dependency will not only advance our understanding of how renal cancer cells bypass ferroptotic cell death to survive and grow but also provide important insights into the development of novel therapeutic strategies to target accompanying metabolic vulnerabilities in RCC. With respect to expected outcomes, our proposed studies will identify novel regulatory mechanisms of ferroptosis pathways, clarify the tumor suppression function of BAP1, and identify new effective therapies to target metabolic vulnerabilities in renal cancer. Our proposal is highly innovative because it focuses on a previously unexplored pathway to link metabolic stress signaling to tumor development and treatment. Our proposed studies will have significant impact on both our understanding of the fundamental mechanisms of metabolic stress response and our ability to target nutrient dependency in renal cancer treatment.