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

Guoqing Zhu,Jiabei Zhu,Miao Ding,Lei Jin,Xiaochen Tang,Ni Zhen,Haojie Li,Qiuhui Pan,Fenyong Sun,Li Liu,Ji Ma,Abduh Murshed,Siwei Mao

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.

Highlights

Ferroptosis is a newly identified form of programmed cell death that is different from apoptosis and necrosis[1], and characterized by iron-dependent accumulation of lipid peroxides[2,3]
O-GlcNAcylation increases the sensitivity of hepatocellular carcinoma (HCC) cells to ferroptosis RSL3 is recognized as a classical small molecule that induces ferroptosis by inhibiting the PL-peroxidase activity of glutathione peroxidase 4 (GPX4)
Since ferroptosis and O-GlcNAcylation are both closely related to metabolism, and high OGlcNAcylation induction leads to an increase in overall cell metabolism, disruption of the balance may cause changes in ferroptosis sensitivity

Summary

Introduction

Ferroptosis is a newly identified form of programmed cell death that is different from apoptosis and necrosis[1], and characterized by iron-dependent accumulation of lipid peroxides[2,3]. OGlcNAcylation often functions as a nutrient sensor to modify multiple aspects of cell physiology, especially in cancer[17]. Cancer cells take up large amounts of nutrients and preferentially use aerobic glycolysis, which greatly increases global O-GlcNAcylation, to adapt to the rapid growth of tumors. We observed elevated O-GlcNAcylation in liver cancer and found that overexpression of OGT facilitated hepatocellular carcinoma (HCC) tumorigenesis[19]. We first found that OGT can modify threonine (Thr) 241 OGlcNAcylation of yes-associated protein (YAP), which is the core factor in the Hippo pathway, to facilitate its transcriptional activity. YAP and O-GlcNAcylation form a harmful axis to promote glucose and lipid metabolism in order to facilitate tumorigenesis

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Results

Conclusion