O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer

Cellular Signalling
Yan ChenFenyong Sun

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 represen...Continue Reading

Citations

Aug 18, 2020·Autophagy·Xin ChenDaolin Tang
Mar 4, 2020·Cancer Gene Therapy·Chongshan DaiDaolin Tang
Dec 30, 2020·Cancer Cell International·Yueyue YangJiayi Wang
Dec 4, 2020·Cell Research·Daolin TangGuido Kroemer
Apr 20, 2021·Frontiers in Oncology·Zhiyuan ShiChen Shao
Jul 13, 2021·European Journal of Pharmacology·Min JiaYulong Chen

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