O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer
O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer
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O-GlcNAcylated c-Jun 通过抑制肝癌中 GSH 合成来拮抗铁死亡
DOI：
10.1016/j.cellsig.2019.109384
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发表时间：
2019-11-01
影响因子：
4.8
通讯作者：
Sun, Fenyong
中科院分区：
文献类型：
--
作者：
Chen, Yan;Zhu, Guoqing;Sun, Fenyong
铁下垂是一种新陈代谢相关的细胞死亡。刺激肝癌细胞的铁性下垂是治疗肝癌的一种策略。然而，如何通过铁性下垂清除肝癌细胞，以及在肝癌中诱导铁性下垂的障碍仍不清楚。在这里，我们观察到erastin通过抑制c-jun的O-GlcN酰化而抑制肝癌细胞的恶性表型，进而抑制c-jun的蛋白表达、转录活性和核积聚。C-Jun-WT的过表达与PuGNAc同时处理可抑制Erastin诱导的铁下垂，而单独c-Jun-WT的过表达或c-Jun-S73A(c-Jun的一种非O-GlcN酰化形式)的过表达与PuGNAc处理没有类似的作用。C-Jun-WT的高表达与PuGNAc同时作用可恢复Erastin诱导的GSH下调。此外，c-Jun-WT的过表达，而不是其S73A突变体，通过直接与它们的启动子区域结合来诱导PSAT1和CBS的转录，表明GSH的合成受O-GlcNacylated c-Jun.临床标本中c-jun O-GlcN酰化与GSH呈正相关。总之，O-GlcNacylated c-jun是铁性下垂的阻碍因子，靶向O-GlcNacylated c-jun可能有助于肝癌的治疗。
Ferroptosis is a metabolism-related cell death. Stimulating ferroptosis in liver cancer cells is a strategy to treat liver cancer. However, how to eradicate liver cancer cells through ferroptosis and the obstacles to inducing ferroptosis in liver cancer remain unclear. Here, we observed that erastin suppressed the malignant phenotypes of liver cancer cells by inhibiting O-GlcNAcylation of c-Jun and further inhibited protein expression, transcription activity and nuclear accumulation of c-Jun. Overexpression of c-Jun-WT with simultaneous PuGNAc treatment conversely inhibited erastin-induced ferroptosis, whereas overexpression of c-Jun-WT alone or overexpression of c-Jun-S73A (a non-O-GlcNAcylated form of c-Jun) with PuGNAc treatment did not exert a similar effect. GSH downregulation induced by erastin was restored by overexpression of c-Jun-WT with simultaneous PuGNAc treatment. In addition, overexpression of c-Jun-WT, but not its S73A mutant, induced PSAT1 and CBS transcription via directly binding to their promoter regions, suggesting that GSH synthesis is regulated by O-GlcNAcylated c-Jun. A positive correlation between c-Jun O-GlcNAcylation and GSH was observed in clinical samples. Collectively, O-GlcNAcylated c-Jun represents an obstructive factor to ferroptosis, and targeting O-GlcNAcylated c-Jun might be helpful for treating liver cancer.