The critical role of SETDB1-mediated CCND1/PI3K/AKT pathway via p53-RS di-methylation at K370 in the proliferation of WRL68 cells induced by nicotine

Zihan Li; Yuqin Xu; Yuxin Hu; Zihan He; Zhongwei Zhang; Jianming Zhou; Tong Zhou; Huai Wang

Ecotoxicology and Environmental Safety (Sep 2024)

The critical role of SETDB1-mediated CCND1/PI3K/AKT pathway via p53-RS di-methylation at K370 in the proliferation of WRL68 cells induced by nicotine

Zihan Li,
Yuqin Xu,
Yuxin Hu,
Zihan He,
Zhongwei Zhang,
Jianming Zhou,
Tong Zhou,
Huai Wang

Affiliations

Zihan Li: School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
Yuqin Xu: School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
Yuxin Hu: School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
Zihan He: School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
Zhongwei Zhang: School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
Jianming Zhou: School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
Tong Zhou: School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China
Huai Wang: School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China; Chongqing Research Institute of Nanchang University, Tai Bai Road, Tongnan, Chongqing 402679, PR China; Corresponding author at: School of Public Health, Jiangxi Medical College, Nanchang University, No. 461 Ba Yi Avenue, Nanchang, Jiangxi 330006, PR China.

Journal volume & issue: Vol. 282
p. 116686

Abstract

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Constituents of cigarette smoke are known to be carcinogens. Additionally, there is mounting evidence that the liver is an organ susceptible to tobacco carcinogenicity. Nicotine, the primary constituent of tobacco, plays a role in cancer progression. In our previous study, it was found that nicotine enhances the proliferation of a human normal fetal hepatic (WRL68) cell due to the activation of p53 mutation at Ser249 (p53-RS)/STAT1/CCND1 signaling pathway. Here, we further elucidated the mechanism of regulating this pathway. Firstly, dose-dependent increase of SETDB1 protein level in WRL68 cells upon exposure to nicotine (1.25, 2.5, and 5 μM), significantly enhanced cellular proliferation. In addition, the upregulation of SETDB1 protein was necessary for the nuclear translocation of p53-RS to establish a ternary complex with STAT1 and SETDB1, which facilitated p53-RS di-methylation at K370 (p53-RS/K370me2). After that, the activation of CCND1/PI3K/AKT pathway was initiated when STAT1 stability was enhanced by p53-RS/K370me2, ultimately resulting in cell proliferation. Altogether, the study revealed that the increase in SETDB1 expression could potentially have a significant impact on the activation of CCND1/PI3K/AKT pathway through p53-RS/K370me2, leading to the proliferation of WRL68 cells induced by nicotine, which could contribute to hepatocellular carcinoma for smokers. Besides, the results of this study provided a foundation for the development of anticancer therapies for cancers associated with tobacco use.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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