The E3 Ligase MIB1 Promotes Proteasomal Degradation of NRF2 and Sensitizes Lung Cancer Cells to Ferroptosis

被引:37
|
作者
Wang, Haiyun [1 ,2 ]
Huang, Qiuling [3 ]
Xia, Jianhong [2 ,3 ]
Cheng, Shan [2 ]
Pei, Duanqing [2 ,3 ]
Zhang, Xiaofei [2 ,3 ]
Shu, Xiaodong [2 ,3 ,4 ]
机构
[1] Univ Sci & Technol China, Sch Life Sci, Hefei, Peoples R China
[2] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, CAS Key Lab Regenerat Biol, Guangdong Prov Key Lab Stem Cell & Regenerat Med, Guangzhou, Peoples R China
[3] Guangzhou Regenerat Med & Hlth Guangdong Lab GRMH, Guangzhou, Peoples R China
[4] Guangzhou Med Univ, Chinese Acad Sci, Joint Sch Life Sci, Guangzhou Inst Biomed & Hlth, Guangzhou, Peoples R China
关键词
UBIQUITIN LIGASE; MIND BOMB; NOTCH; ACTIVATION;
D O I
10.1158/1541-7786.MCR-21-0342
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Dysregulation of Notch signaling has been implicated in cellular transformation and tumorigenesis in a variety of cancers while potential roles of MIB1, an E3 ubiquitin ligase required for efficient Notch activation, remains to be investigated. We analyzed MIB1 expression levels in tumor samples and performed gain-of-function and loss-of-function studies in cell lines to investigate potential roles of MIB1 in epithelial-to-mesenchymal transition (EMT), cell migration, and cell survival. We found that overexpression of MIB1 is detected in a subset of lung squamous carcinoma and adenocarcinoma samples and negative correlation is observed between MIB1 expression and overall patient survival. Ectopic expression of MIB1 in A549 cells induces EMT and stimulates cell migration via a Notch-dependent pathway. Meanwhile, MIB1 stimulates the degradation of nuclear factor erythroid 2-related factor 2 (NRF2) in a Notch-independent manner and disrupts the antioxidant capacity of cells, rendering them more sensitive to inducers of ferroptosis. On the other hand, MIB1 knockout induces accumulation of NRF2 and resistance to ferroptosis. Collectively, these results indicate that MIB1 may function as a positive regulator of ferroptosis through targeted degradation of the master antioxidant transcription factor NRF2.
引用
收藏
页码:253 / 264
页数:12
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