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，并且几种众所周知的肾癌基因是 参与代谢应激反应的途径。因此，迫切需要了解代谢 强调参与RCC发展的途径，并开发针对基础代谢的治疗方法， RCC中的漏洞。BAP 1在RCC中作为肿瘤抑制基因，在高达15%的患者中存在失活突变。 的病例和透明细胞RCC（ccRCC）的频繁缺失，BAP 1突变型ccRCC患者表现出 尤其是临床效果不佳。然而，BAP 1如何在肾癌中作为肿瘤抑制因子发挥作用仍是一个未知数。 目前还没有有效的治疗方法来治疗BAP 1突变的RCC患者。BAP 1及其 相关蛋白形成多梳抑制性去泛素化酶（PR-DUB）复合物，其减少组蛋白2A 泛素化（H2 Aub）在染色质上的作用，并调节基因转录。SLC 7A 11是一种胱氨酸转运蛋白。我们 最近的出版物和初步数据将BAP 1与SLC 7A 11联系起来，并支持我们的中心假设。 建议（i）含有BAP 1的PR-DUB复合物介导H2 Aub去泛素化和转录 SLC 7A 11的抑制和BAP 1缺陷或PR-DUB复合物中其他组分的改变， 抑制SLC 7A 11表达，使肾癌细胞对铁凋亡（一种非凋亡细胞）更有抵抗力 代谢应激诱导的死亡）并促进RCC发展;和（ii）BAP 1缺陷/突变型肾 肿瘤的存活更依赖于葡萄糖，部分原因是这些肿瘤中的高SLC 7A 11表达， 从而暴露出用于治疗靶向的代谢弱点。在这项建议中，我们将采用多学科 测试我们假设的方法。拟议研究的基本原理是研究 BAP 1-SLC 7A 11信号轴在铁凋亡和葡萄糖依赖中的作用不仅将促进我们对 肾癌细胞如何绕过铁凋亡细胞的死亡而存活和生长， 开发新的治疗策略，以靶向RCC中伴随的代谢脆弱性。 关于预期的结果，我们提出的研究将确定新的调节机制的铁凋亡 研究BAP 1的肿瘤抑制功能，并确定新的有效疗法，以靶向代谢途径， 肾癌的脆弱性。我们的建议是高度创新的，因为它侧重于一个以前未探索的 将代谢应激信号传导与肿瘤发展和治疗联系起来的途径。我们提出的研究将有 对我们理解代谢应激反应的基本机制和 我们在肾癌治疗中靶向营养依赖的能力。

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.