泛素结合酶UBE2S调控GPX4/SLC7A11影响肝癌细胞铁死亡的机制研究

我们最近报道了泛素结合酶UBE2S在肝癌患者中高表达，且其高表达与肝癌患者生存率降低相关。预实验发现，索拉非尼处理肝癌细胞后，UBE2S敲减组中细胞死亡数目增多，且该组中的细胞死亡可被铁死亡抑制剂挽救；生信分析与WB预实验表明UBE2S表达与GPX4/SLC7A11呈正相关。提示UBE2S可能调控GPX4/SLC7A11抑制肝癌细胞铁死亡，但机理不清。STRING数据库显示UBE2S可与去泛素化酶OTUB1结合，已有研究表明UBE2S可增强p53泛素化，而p53抑制SLC7A11转录。在此基础上，本项目拟通过细胞和动物实验研究UBE2S对肝癌细胞铁死亡的调控作用；探讨UBE2S是否通过结合OTUB1稳定GPX4；验证UBE2S是否通过增强p53泛素化促进SLC7A11表达。本项目的完成，将阐明UBE2S调控GPX4/SLC7A11影响肝癌细胞铁死亡的分子机制，并为肝癌治疗提供新的理论基础。

We recently reported that ubiquitin-conjugating enzyme E2 S(UBE2S) was highly expressed in patients with liver cancer, and its high expression was significantly associated with poor survival. Pre-experiments found that high levels of cell death were observed upon sorafenib induction in all UBE2S knockdown cells relative to control cells, and cell death was inhibited by the ferroptosis inhibitor. Bioinformatics analysis and western blot results showed UBE2S expression was positively correlated with GPX4/SLC7A11 expression. These studies imply that UBE2S is involved in the negative regulation of ferroptosis via GPX4/SLC7A11. However, the mechanism is unclear. The STRING database shows that UBE2S binds to OTUB1. Studies have shown that UBE2S enhances ubiquitination of p53, and p53 inhibits SLC7A11 transcription. We aim to clarify the regulatory effect of UBE2S on ferroptosis in liver cancer cells through cell lines and nude mice, investigate whether UBE2S stabilizes GPX4 by binding OTUB1, and identify whether UBE2S promotes SLC7A11 expression by enhancing the ubiquitination of p53. This study will elucidate the molecular mechanism by which UBE2S mediates ferroptosis in liver cancer cells via GPX4/SLC7A11. Meanwhile, it provides a novel strategy for the treatment of liver cancer.