O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer

  • Cell Death Discov. 2021 Apr 16;7(1):83. doi: 10.1038/s41420-021-00468-2.
Guoqing Zhu   #  1 ,  Abduh Murshed   #  2 ,  Haojie Li  2 ,  Ji Ma  1 ,  Ni Zhen  1 ,  Miao Ding  1 ,  Jiabei Zhu  1 ,  Siwei Mao  1 ,  Xiaochen Tang  1 ,  Li Liu  3 ,  Fenyong Sun  2 ,  Lei Jin  4 ,  Qiuhui Pan  5
Affiliations
  • 1. Department of Clinical Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, 200127, Shanghai, China.
  • 2. Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, 200072, Shanghai, China.
  • 3. Department of Clinical Laboratory, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, 200434, Shanghai, China.
  • 4. Faculty of Medical Laboratory, Shanghai University of Medicine and Health Sciences, 201318, Shanghai, China. [email protected].
  • 5. Department of Clinical Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, 200127, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 33863873 DOI: 10.1038/s41420-021-00468-2
Abstract

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.

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