蛋白质精氨酸甲基转移酶5
三阴性乳腺癌
免疫疗法
癌症研究
KEAP1型
癌症免疫疗法
免疫系统
癌症
乳腺癌
医学
化学
免疫学
生物
甲基转移酶
甲基化
内科学
生物化学
转录因子
基因
作者
Zhe Wang,Ruolei Li,Niuniu Hou,Juliang Zhang,Ting Wang,Pengyu Fan,Jian Cheng,Chao Zhang,Liuyin Liu,Ya-Ping Wang,Jing Kong,Qing Yao,Jie Duan,Guiqiu Zhao,Rui Ling,Jian Zhang
标识
DOI:10.1136/jitc-2023-006890
摘要
As an emerging treatment strategy for triple-negative breast cancer (TNBC), immunotherapy acts in part by inducing ferroptosis. Recent studies have shown that protein arginine methyltransferase 5 (PRMT5) has distinct roles in immunotherapy among multiple cancers by modulating the tumor microenvironment. However, the role of PRMT5 during ferroptosis, especially for TNBC immunotherapy, is unclear.PRMT5 expression in TNBC was measured by IHC (immunohistochemistry) staining. To explore the function of PRMT5 in ferroptosis inducers and immunotherapy, functional experiments were conducted. A panel of biochemical assays was used to discover potential mechanisms.PRMT5 promoted ferroptosis resistance in TNBC but impaired ferroptosis resistance in non-TNBC. Mechanistically, PRMT5 selectively methylated KEAP1 and thereby downregulated NRF2 and its downstream targets which can be divided into two groups: pro-ferroptosis and anti-ferroptosis. We found that the cellular ferrous level might be a critical factor in determining cell fate as NRF2 changes. In the context of higher ferrous concentrations in TNBC cells, PRMT5 inhibited the NRF2/HMOX1 pathway and slowed the import of ferrous. In addition, a high PRMT5 protein level indicated strong resistance of TNBC to immunotherapy, and PRMT5 inhibitors potentiated the therapeutic efficacy of immunotherapy.Our results reveal that the activation of PRMT5 can modulate iron metabolism and drive resistance to ferroptosis inducers and immunotherapy. Accordingly, PRMT5 can be used as a target to change the immune resistance of TNBC.
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