Zhu Guoqing, Murshed Abduh, Li Haojie, Ma Ji, Zhen Ni, Ding Miao, Zhu Jiabei, Mao Siwei, Tang Xiaochen, Liu Li, Sun Fenyong, Jin Lei, Pan Qiuhui
Department of Clinical Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, 200127, Shanghai, China.
Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, 200072, Shanghai, China.
Cell Death Discov. 2021 Apr 16;7(1):83. doi: 10.1038/s41420-021-00468-2.
Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. YAP has been reported to play a pivotal role in controlling ferroptotic death, and the expression of YAP is enhanced and stabilized by O-GlcNAcylation. However, whether O-GlcNAcylation can increase the sensitivity of hepatocellular carcinoma (HCC) cells to ferroptosis remains unknown. In the present study, we found that O-GlcNAcylation increased the sensitivity of HCC cells to ferroptosis via YAP. Moreover, YAP increased the iron concentration in HCC cells through transcriptional elevation of TFRC via its O-GlcNAcylation. With YAP knockdown or YAP-T241 mutation, the increased sensitivity to ferroptosis induced by O-GlcNAcylation was abolished. In addition, the xenograft assay confirmed that O-GlcNAcylation increased ferroptosis sensitivity via TFRC in vivo. In summary, we are the first to find that O-GlcNAcylation can increase ferroptosis sensitivity in HCC cells via YAP/TFRC. Our work will provide a new basis for clinical therapeutic strategies for HCC patients.
铁死亡是一种程序性细胞死亡形式，其特征是脂质氢过氧化物在铁依赖性作用下积累至致死水平。据报道，Yes相关蛋白（YAP）在控制铁死亡中起关键作用，且O-连接的N-乙酰葡糖胺糖基化（O-GlcNAcylation）可增强并稳定YAP的表达。然而，O-GlcNAcylation是否能增加肝癌（HCC）细胞对铁死亡的敏感性仍不清楚。在本研究中，我们发现O-GlcNAcylation通过YAP增加了HCC细胞对铁死亡的敏感性。此外，YAP通过其O-GlcNAcylation转录上调转铁蛋白受体（TFRC），从而增加了HCC细胞中的铁浓度。敲低YAP或YAP-T241突变后，O-GlcNAcylation诱导的对铁死亡增加的敏感性被消除。此外，异种移植试验证实，O-GlcNAcylation在体内通过TFRC增加了铁死亡敏感性。总之，我们首次发现O-GlcNAcylation可通过YAP/TFRC增加HCC细胞对铁死亡的敏感性。我们的工作将为HCC患者的临床治疗策略提供新的依据。
