Nestin regulates cellular redox homeostasis in lung cancer through the Keap1–Nrf2 feedback loop

Jiancheng Wang, Qiying Lu, Jianye Cai, Yi Wang, Xiaofan Lai, Yuan Qiu, Yinong Huang, Qiong Ke, Yanan Zhang, Yuanjun Guan, Haoxiang Wu, Yuanyuan Wang, Xin Liu, Yue Shi, Kang Zhang, Maosheng Wang () and Andy Peng Xiang ()
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Jiancheng Wang: Sun Yat-Sen University
Qiying Lu: Sun Yat-Sen University
Jianye Cai: Sun Yat-Sen University
Yi Wang: Sun Yat-Sen University
Xiaofan Lai: The First Affiliated Hospital of Sun Yat-sen University
Yuan Qiu: Sun Yat-Sen University
Yinong Huang: Sun Yat-Sen University
Qiong Ke: Sun Yat-Sen University
Yanan Zhang: Sun Yat-Sen University
Yuanjun Guan: Sun Yat-Sen University
Haoxiang Wu: Sun Yat-Sen University
Yuanyuan Wang: Sun Yat-Sen University
Xin Liu: Sun Yat-Sen University
Yue Shi: Sun Yat-Sen University
Kang Zhang: Macau University of Science and Technology
Maosheng Wang: Gaozhou People’s Hospital
Andy Peng Xiang: Sun Yat-Sen University

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12925-9

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