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Nat Commun. 2019 Nov 6;10(1):5043. doi: 10.1038/s41467-019-12925-9.

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

Wang J1,2, Lu Q1,2, Cai J2,3, Wang Y1,2, Lai X4, Qiu Y1,2, Huang Y2,5, Ke Q1,2, Zhang Y1,2, Guan Y6, Wu H2, Wang Y2, Liu X2, Shi Y2, Zhang K7, Wang M8, Peng Xiang A9,10,11,12,13.

Author information

1
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
2
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
3
Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-Sen University, Guangzhou, China.
4
Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
5
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
6
Core Facility of Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
7
Faculty of Medicine, Macau University of Science and Technology, Macau, China.
8
The Cardiovascular Center, Gaozhou People's Hospital, Maoming, China. mmwmsmd@126.com.
9
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. xiangp@mail.sysu.edu.cn.
10
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China. xiangp@mail.sysu.edu.cn.
11
Core Facility of Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. xiangp@mail.sysu.edu.cn.
12
Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. xiangp@mail.sysu.edu.cn.
13
Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China. xiangp@mail.sysu.edu.cn.

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.

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