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

Abstract

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.