PMID- 34670864
OWN - NLM
STAT- MEDLINE
DCOM- 20220330
LR  - 20220330
IS  - 1557-3125 (Electronic)
IS  - 1541-7786 (Linking)
VI  - 20
IP  - 2
DP  - 2022 Feb
TI  - The E3 Ligase MIB1 Promotes Proteasomal Degradation of NRF2 and Sensitizes Lung 
      Cancer Cells to Ferroptosis.
PG  - 253-264
LID - 10.1158/1541-7786.MCR-21-0342 [doi]
AB  - 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. IMPLICATIONS: This study identifies a MIB1-induced 
      proteasomal degradation pathway for NRF2 and reveals elevated ferroptosis 
      sensitivity in MIB1-overexpressing cells which may provide novel insights into 
      the treatment of MIB1-overexpressing cancers.
CI  - (c)2021 American Association for Cancer Research.
FAU - Wang, Haiyun
AU  - Wang H
AD  - School of Life Sciences, University of Science and Technology of China, Hefei, 
      P.R. China.
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, P.R. China.
FAU - Huang, Qiuling
AU  - Huang Q
AD  - Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), 
      Guangzhou, P.R. China.
FAU - Xia, Jianhong
AU  - Xia J
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, P.R. China.
AD  - Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), 
      Guangzhou, P.R. China.
FAU - Cheng, Shan
AU  - Cheng S
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, P.R. China.
FAU - Pei, Duanqing
AU  - Pei D
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, P.R. China.
AD  - Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), 
      Guangzhou, P.R. China.
FAU - Zhang, Xiaofei
AU  - Zhang X
AUID- ORCID: 0000-0002-2564-9258
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, P.R. China.
AD  - Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), 
      Guangzhou, P.R. China.
FAU - Shu, Xiaodong
AU  - Shu X
AD  - CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory 
      of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and 
      Health, Chinese Academy of Sciences, Guangzhou, P.R. China. 
      shu_xiaodong@gibh.ac.cn.
AD  - Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), 
      Guangzhou, P.R. China.
AD  - Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, 
      Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, P.R. China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211020
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (NF-E2-Related Factor 2)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Animals
MH  - Ferroptosis/*genetics
MH  - Humans
MH  - Lung Neoplasms/*genetics
MH  - Mice
MH  - Mice, Knockout
MH  - NF-E2-Related Factor 2/*genetics
MH  - Transfection
MH  - Ubiquitin-Protein Ligases/*metabolism
MH  - Zebrafish
EDAT- 2021/10/22 06:00
MHDA- 2022/03/31 06:00
CRDT- 2021/10/21 05:43
PHST- 2021/05/10 00:00 [received]
PHST- 2021/08/31 00:00 [revised]
PHST- 2021/10/13 00:00 [accepted]
PHST- 2021/10/22 06:00 [pubmed]
PHST- 2022/03/31 06:00 [medline]
PHST- 2021/10/21 05:43 [entrez]
AID - 1541-7786.MCR-21-0342 [pii]
AID - 10.1158/1541-7786.MCR-21-0342 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2022 Feb;20(2):253-264. doi: 10.1158/1541-7786.MCR-21-0342. Epub 
      2021 Oct 20.