Repeated PM2.5 exposure inhibits BEAS-2B cell P53 expression through ROS-Akt-DNMT3B pathway-mediated promoter hypermethylation
Metrics: PDF 2397 views | HTML 3779 views | ?
Wei Zhou1, Dongdong Tian1, Jun He1, Yimei Wang1, Lijun Zhang1, Lan Cui1, Li Jia1, Li Zhang1, Lizhong Li1, Yulei Shu1, Shouzhong Yu1, Jun Zhao1, Xiaoyan Yuan1, Shuangqing Peng1
1Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, PR China
Xiaoyan Yuan, email: [email protected]
Shuangqing Peng, email: [email protected]
Keywords: PM2.5, Akt, DNMT3B, P53, hypermethylation
Received: September 30, 2015 Accepted: February 06, 2016 Published: March 02, 2016
Long-term exposure to fine particulate matter (PM2.5) has been reported to be closely associated with the increased lung cancer risk in populations, but the mechanisms underlying PM-associated carcinogenesis are not yet clear. Previous studies have indicated that aberrant epigenetic alterations, such as genome-wide DNA hypomethylation and gene-specific DNA hypermethylation contribute to lung carcinogenesis. And silence or mutation of P53 tumor suppressor gene is the most prevalent oncogenic driver in lung cancer development. To explore the effects of PM2.5 on global and P53 promoter methylation changes and the mechanisms involved, we exposed human bronchial epithelial cells (BEAS-2B) to low concentrations of PM2.5 for 10 days. Our results indicated that PM2.5-induced global DNA hypomethylation was accompanied by reduced DNMT1 expression. PM2.5 also induced hypermethylation of P53 promoter and inhibited its expression by increasing DNMT3B protein level. Furthermore, ROS-induced activation of Akt was involved in PM2.5-induced increase in DNMT3B. In conclusion, our results strongly suggest that repeated exposure to PM2.5 induces epigenetic silencing of P53 through ROS-Akt-DNMT3B pathway-mediated promoter hypermethylation, which not only provides a possible explanation for PM-induced lung cancer, but also may help to identify specific interventions to prevent PM-induced lung carcinogenesis.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.