铁死亡是新近发现的一种新型细胞死亡方式，在肿瘤中发挥重要作用。但铁死亡的调控机制很不清楚，其细胞核机制更是知之甚少。为了探讨以组蛋白修饰为代表的细胞核事件是否调控铁死亡，申请人系统筛选了Erastin诱导铁死亡中不同组蛋白修饰的动态变化，发现H2B单泛素化（H2Bub1）的水平显著下降。抑制内源H2Bub1，可使细胞对Erastin的敏感性增加，更易发生铁死亡。申请人还发现，p53是一个新的H2Bub1负调控蛋白，在Erastin诱导的H2Bub1下调中起关键作用。申请人将在这些工作基础上，利用分子细胞生物学和肿瘤行为学等实验，进一步研究p53调控H2Bub1的机制以及p53-H2Bub1调控轴在铁死亡和肿瘤中的作用和机制。本项目将阐明新的调控铁死亡和肿瘤的信号途径，加深对铁死亡和肿瘤表观遗传机制的理解，拓宽对H2Bub1生物学功能的认识，为基于铁死亡表观遗传调控的肿瘤治疗提供理论依据。

Ferroptosis is a recently identified novel type of cell death, which plays significant roles in multiple diseases including cancer. However, the molecular mechanisms of ferroptosis are largely unclear, especially the mechanisms regulated by nuclear events. To know whether epigenetic pathways are involved in ferroptosis, the applicant performed a screen to determine the changes of different histone modifications during erastin-induced ferroptosis. The result showed that the levels of histone H2B monoubiquitination (H2Bub1) are decreased strikingly. Cells depleted with endogenous H2Bub1 are more sensitive to erastin-induced cell death. Moreover, the applicant found that p53 is a novel negative regulator of H2Bub1 and is essential for erastin-induced H2Bub1 decrease. Based on these original data, the applicant will systematically study the molecular mechanisms of the regulation of H2Bub1 by p53, and roles of p53-H2Bub1 axis in the control of ferroptosis and tumorigenesis. This project will determine a novel regulatory pathway of ferroptosis by an epigenetic event. In addition, this project will also provide significant contributions on the global understanding of the biological roles of H2Bub1, and help us to improve the targeted molecule therapy for cancer patients.