食管鳞癌中ZNF750调控铁死亡的作用和机制

食管鳞癌是我国高发恶性肿瘤，临床预后极差。铁死亡是铁离子依赖的脂质过氧化导致的程序性细胞死亡方式，在食管鳞癌中尚无深入研究。ZNF750是新的食管鳞癌相关基因，在食管鳞癌中通过抑制EMT发挥抑癌作用，其突变/低表达和患者预后差显著相关。初步实验发现ZNF750低表达的食管鳞癌细胞对铁死亡诱导剂更敏感，转录组数据提示ZNF750调控基因富集于脂质代谢途径，其中脂质代谢基因暨铁死亡关键基因ACSF2、ACSL4的表达受ZNF750调控，ChIP显示ZNF750可结合二者启动子区域，提示ZNF750可能通过调控脂质代谢进而调控铁死亡，但具体机制尚不清楚。本项目拟通过体内外实验、代谢组学和脂质组学研究ZNF750对铁死亡的影响及调控机制，检测不同ZNF750基因型食管鳞癌细胞对铁死亡的敏感性，从而探索ZNF750在食管鳞癌铁死亡中的调控作用，为发现食管鳞癌新的治疗靶点、实现精准治疗提供理论依据。

Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal carcinoma in China, with poor prognosis because of late diagnosis and limited therapeutic method. Ferroptosis is a newly defined form of programmed cell death characterized by the iron-dependent accumulation of lipid hydroperoxides and plays an important role in the oncogenesis and development of cancer. Our previous study showed that ZNF750, a novel ESCC-related gene, harbors significant inactivation mutations in ESCC. Its mutation or deletion was indicated poor survival of ESCC patients. Further studies showed that ZNF750 may act as a tumor suppressor via inhibition of SNAI1 and EMT in ESCC. And we found ESCC cells with ZNF750-knockdown were more sensitive to ferroptosis inducers. Transcriptome analysis showed the downstream genes of ZNF750 were enriched in the lipid metabolic process. Among them, ACSL4 and ACSF2, which are two key genes in the lipid metabolic process and play important roles in ferroptosis, were regulated by ZNF750. Meanwhile, the results of chromatin immunoprecipitation showed ZNF750 could directly bind to the promoter regions of the two key genes involved in ferroptosis. These results suggested ZNF750 might play an important role in the ferroptosis process via regulating lipid metabolism, and ferroptosis inducers might be used in the treatment of ESCC patients with different ZNF750 status. However, the mechanism remains unclear. This proposal aims to validate the role of ZNF750 in the process of ferroptosis in ESCC and further to reveal its molecular mechanism via experiments in vitro and in vivo, metabolomics and lipidomics. These results will facilitate early diagnosis, prevention, and precise treatment of ESCC in the Chinese population.