Homocysteine‐potentiated Kelch‐like ECH‐associated protein 1 promotes senescence of neuroblastoma 2a cells via inhibiting ubiquitination of β‐catenin

Author:

Zhang Yao1,Xie Jia‐Zhao23,Jiang Yan‐Li4,Yang Shao‐Juan4,Wei Hui2,Yang Ying2,Wang Jian‐Zhi25

Affiliation:

1. Endocrine Department of Liyuan Hospital; Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College Huazhong University of Science and Technology Wuhan China

2. Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College Huazhong University of Science and Technology Wuhan China

3. Precision Medical Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College Huazhong University of Science & Technology Wuhan China

4. Endocrine Department of Liyuan Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China

5. Co‐innovation Center of Neuroregeneration Nantong University Nantong China

Abstract

AbstractElevated serum homocysteine (Hcy) level is a risk factor for Alzheimer's disease (AD) and accelerates cell aging. However, the mechanism by which Hcy induces neuronal senescence remains largely unknown. In this study, we observed that Hcy significantly promoted senescence in neuroblastoma 2a (N2a) cells with elevated β‐catenin and Kelch‐like ECH‐associated protein 1 (KEAP1) levels. Intriguingly, Hcy promoted the interaction between KEAP1 and the Wilms tumor gene on the X chromosome (WTX) while hampering the β‐catenin‐WTX interaction. Mechanistically, Hcy attenuated the methylation level of the KEAP1 promoter CpG island and activated KEAP1 transcription. However, a slow degradation rate rather than transcriptional activation contributed to the high level of β‐catenin. Hcy‐upregulated KEAP1 competed with β‐catenin to bind to WTX. Knockdown of both β‐catenin and KEAP1 attenuated Hcy‐induced senescence in N2a cells. Our data highlight a crucial role of the KEAP1‐β‐catenin pathway in Hcy‐induced neuronal‐like senescence and uncover a promising target for AD treatment.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Publisher

Wiley

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