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- Title
Nestin regulates cellular redox homeostasis in lung cancer through the Keap1–Nrf2 feedback loop.
- Authors
Wang, Jiancheng; Lu, Qiying; Cai, Jianye; Wang, Yi; Lai, Xiaofan; Qiu, Yuan; Huang, Yinong; Ke, Qiong; Zhang, Yanan; Guan, Yuanjun; Wu, Haoxiang; Wang, Yuanyuan; Liu, Xin; Shi, Yue; Zhang, Kang; Wang, Maosheng; Peng Xiang, Andy
- Abstract
Abnormal cancer antioxidant capacity is considered as a potential mechanism of tumor malignancy. Modulation of oxidative stress status is emerging as an anti-cancer treatment. Our previous studies have found that Nestin-knockdown cells were more sensitive to oxidative stress in non-small cell lung cancer (NSCLC). However, the molecular mechanism by which Nestin protects cells from oxidative damage remains unclear. Here, we identify a feedback loop between Nestin and Nrf2 maintaining the redox homeostasis. Mechanistically, the ESGE motif of Nestin interacts with the Kelch domain of Keap1 and competes with Nrf2 for Keap1 binding, leading to Nrf2 escaping from Keap1-mediated degradation, subsequently promoting antioxidant enzyme generation. Interestingly, we also map that the antioxidant response elements (AREs) in the Nestin promoter are responsible for its induction via Nrf2. Taken together, our results indicate that the Nestin–Keap1–Nrf2 axis regulates cellular redox homeostasis and confers oxidative stress resistance in NSCLC. Loss of Nestin sensitizes non-small cell lung carcinoma (NSCLC) to oxidative stress. Here, the authors report a feedback loop between Nestin and Nrf2 wherein Nestin competes with Nrf2 for Keap1 binding, preventing Nrf2 degradation, and show the Nestin–Keap1–Nrf2 axis to regulate redox homeostasis in NSCLC.
- Subjects
HOMEOSTASIS; LUNG cancer; OXIDANT status; CANCER treatment; OXIDATIVE stress
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-12925-9