Neddylation修饰阻滞LSD1泛素化降解促进肺癌放疗抵抗的作用和机制研究

放疗抵抗是肺癌治疗失败和疾病进展的重要因素，解析放疗抵抗的发生机制有助于寻求新型有效的放疗增敏手段。LSD1是第一个被发现的蛋白质去甲基化酶，通过催化组蛋白和非组蛋白的去甲基化过程而发挥重要的生物学功能。近来研究表明，LSD1在DNA损伤应答中发挥重要作用，但其是否参与肺癌放疗抵抗的发生，目前未知。而LSD1的上游调控机制特别是翻译后修饰，目前也不清晰。我们前期工作提示，LSD1可能是肺癌产生放疗抵抗的关键因子。机制上，DNA损伤应激使LSD1发生拟素化修饰阻滞其泛素化降解以表达上调进而促进NHEJ修复。本项目将研究1）放疗对LSD1表达的影响；2）LSD1发生拟素化修饰阻滞泛素化降解的分子机制；3）LSD1拟素化修饰在肺癌细胞NHEJ修复及放疗抵抗中的功能。研究结果以期明确LSD1在肺癌放疗抵抗中的作用及其被拟素化修饰调控的新机制，为靶向LSD1提高肿瘤放疗疗效提供理论基础。

Radiation resistance is a crucial determinant for the treatment failure and disease progression of lung cancer. Dissecting the molecular mechanisms of radiation resistance is helpful for developing novel and effective strategies of radiation sensitization. LSD1 (Lysine-specific demethylase 1) is the first identified histone demethylase, it is actively involved in vast range of biological processes through regulating the methylation status of histones and non-histone proteins. Recently, it was reported that LSD1 is involved in DNA damage response, however, whether LSD1 is involved in the development of radiation resistance, and how does LSD1 be regulated in the upstream, especially the post-translational modification, remain elusive. Our preliminary data showed that LSD1 may play pivotal roles in the radiation resistance development of lung cancer. Mechanically, 1) DNA damage stress triggers ATM-mediated neddylation modification of LSD1, which antagonizes its ubiquitylation and degradation; 2) The upregulated LSD1 further facilitates non-homologous end-joining (NHEJ) repair. In this proposal, we will explore 1) The effect of radiation on expression of LSD1; 2) LSD1 is post-translationally modified by neddylation and the involved molecular mechanism; 3) Functions of LSD1 and its neddylation modification in NHEJ repair and radiation resistance of lung cancer. Our proposed study aims to reveal a novel regulation of LSD1 by neddylation pathway and determine its involvement in radiation resistance development, providing new insights into mechanism and rational approaches to radiation of cancer by targeting LSD1.