Targeting N-glycosylation of 4F2hc mediated by glycosyltransferase B3GNT3 sensitizes ferroptosis of pancreatic ductal adenocarcinoma

作者：Heng Ma, Xianlong Chen, Shengwei Mo, Yue Zhang, Xinxin Mao, Jingci Chen, Jingci Chen, Y. Liu, Wei‐Min Tong, Shuangni Yu, Shuangni Yu, Jie Chen, Jie Chen · 发表于：Cell Death and Differentiation · 年份：2023 · DOI：10.1038/s41418-023-01188-z · 被引用次数：54 · 研究领域：Ferroptosis and cancer prognosis、RNA modifications and cancer、Epigenetics and DNA Methylation

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal malignancy partially due to the acquired alterations related to aberrant protein glycosylation that pathologically remodel molecular biological processes and protect PDAC cells from death. Ferroptosis driven by lethal lipid peroxidation provides a targetable vulnerability for PDAC. However, the crosstalk between glycosylation and ferroptosis remains unclear. Here, we identified 4F2hc, a subunit of the glutamate-cystine antiporter system X c – , and its asparagine ( N )-glycosylation is involved in PDAC ferroptosis by N - and O -linked glycoproteomics. Knockdown of SLC3A2 (gene name of 4F2hc) or blocking the N -glycosylation of 4F2hc potentiates ferroptosis sensitization of PDAC cells by impairing the activity of system X c – manifested by a marked decrease in intracellular glutathione. Mechanistically, we found that the glycosyltransferase B3GNT3 catalyzes the glycosylation of 4F2hc, stabilizes the 4F2hc protein, and enhances the interaction between 4F2hc and xCT. Knockout of B3GNT3 or deletion of enzymatically active B3GNT3 sensitizes PDAC cells to ferroptosis. Reconstitution of 4F2hc-deficient cells with wildtype 4F2hc restores ferroptosis resistance while glycosylation-mutated 4F2hc does not. Additionally, upon combination with a ferroptosis inducer, treatment with the classical N -glycosylation inhibitor tunicamycin (TM) markedly triggers the overactivation of lipid peroxidation and enhances the sensi...