The deubiquitinase USP11 regulates cell proliferation and ferroptotic cell death via stabilization of NRF2 USP11 deubiquitinates and stabilizes NRF2

The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a key role in cancer progression and is tightly regulated by the proteasome pathway. E3 ligases that mediate NRF2 ubiquitination have been widely reported, but the mechanism of NRF2 deubiquitination remains largely unc...

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Bibliographic Details
Published in:Oncogene 2021-03, Vol.40 (9), p.1706-1720
Main Authors: Meng, Chunjie, Zhan, Jun, Chen, Delin, Shao, Genze, Zhang, Hongquan, Gu, Wei, Luo, Jianyuan
Format: Article
Language:English
Subjects:
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Apoptosis
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Cell Biology
Cell death
Cell growth
Cell Nucleus - genetics
Cell proliferation
Cell Proliferation - genetics
Deubiquitinating Enzymes - genetics
DNA microarrays
Ferroptosis
Human Genetics
Humans
Internal Medicine
Medicine
Medicine & Public Health
NF-E2-Related Factor 2 - genetics
Non-small cell lung carcinoma
Oncology
Oxidative Stress - genetics
Proteasome Endopeptidase Complex
Proteasomes
Reactive Oxygen Species - metabolism
Signal Transduction - genetics
Thiolester Hydrolases - genetics
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Ubiquitination
Ubiquitination - genetics
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Summary:The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a key role in cancer progression and is tightly regulated by the proteasome pathway. E3 ligases that mediate NRF2 ubiquitination have been widely reported, but the mechanism of NRF2 deubiquitination remains largely unclear. Here, we identified ubiquitin-specific-processing protease 11 (USP11) in NRF2 complexes and confirmed an interaction between these two proteins. We further found that USP11 deubiquitinates NRF2; this modification stabilizes NRF2. Functionally, USP11 depletion contributes to the suppression of cell proliferation and induction of ferroptotic cell death due to ROS-mediated stress, which can be largely abrogated by overexpression of NRF2. Finally, immunohistochemical staining of USP11 and NRF2 was performed using a lung tissue microarray, which revealed that USP11 is highly expressed in patients with NSCLC and positively correlated with NRF2 expression. Together, USP11 stabilizes NRF2 and is thus an important player in cell proliferation and ferroptosis.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-021-01660-5