2. Academic Validation
  3. 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

  • Cell Signal. 2019 Nov;63:109384. doi: 10.1016/j.cellsig.2019.109384.
Yan Chen 1,  Guoqing Zhu 1,  Ya Liu 1,  Qi Wu 1,  Xiao Zhang 2,  Zhixuan Bian 3,  Yue Zhang 4,  Qiuhui Pan 5,  Fenyong Sun 6
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
  • 2 Shanghai Institute of Thoracic Tumors, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200030, China.
  • 3 Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
  • 4 Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
  • 5 Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China. Electronic address: panqiuhui@263.net.
  • 6 Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China. Electronic address: sunfenyongtongji@126.com.
PMID: 31394193 DOI: 10.1016/j.cellsig.2019.109384
Abstract

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.

Keywords

Erastin; Glutathione; O-GlcNAcylation; Phosphorylation; Promoter; Transcription.

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