IL-8 suppresses E-cadherin expression in nasopharyngeal carcinoma cells by enhancing E-cadherin promoter DNA methylation

Zhang,Rui-Li; Peng,Li-Xia; Yang,Jun-Ping; Zheng,Li-Sheng; Xie,Ping; Wang,Meng-Yao; Huang,Bi-Jun; Zhao,Hua-Rong; Bao,Yong-Xing; Qian,Chao-Nan

doi:10.3892/ijo.2015.3226

IL-8 suppresses E-cadherin expression in nasopharyngeal carcinoma cells by enhancing E-cadherin promoter DNA methylation

Authors:
- Rui-Li Zhang
- Li-Xia Peng
- Jun-Ping Yang
- Li-Sheng Zheng
- Ping Xie
- Meng-Yao Wang
- Bi-Jun Huang
- Hua-Rong Zhao
- Yong-Xing Bao
- Chao-Nan Qian
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Affiliations: Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. China, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P.R. China
Published online on: November 2, 2015 https://doi.org/10.3892/ijo.2015.3226
Pages: 207-214

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Abstract

Nasopharyngeal carcinoma (NPC) has the highest metastasis potential among head and neck cancers. Distant metastasis is the major cause of treatment failure. Recent studies from our laboratory have revealed that IL-8 promotes NPC metastasis via activation of AKT signaling and induction of epithelial-mesenchymal transition (EMT) in the cells. In the present study, we found that IL-8 treatment for NPC cells resulted in an accumulation of DNMT1 protein through activating AKT1 pathway and consequent DNMT1 protein stabilization. Then DNMT1 suppressed E-cadherin expression by increasing the methylation of its promoter region. LY-294002 blocked IL-8-induced p-AKT1 activation resulting in reduction of DNMT1 and increase of E-cadherin expression, whereas forced demethylation using 5-aza-2'-deoxycytidine restored E-cadherin expression. In conclusion, our study, for the first time, shows that the IL-8/AKT1 signaling pathway stabilizes DNMT1 protein, consequently enhancing hypermethylation of E-cadherin promoter regions and downregulating E-cadherin protein level in NPC cells. Upon blockage of the IL-8/AKT pathway and inhibition of DNMT1, E-cadherin expression can be reversed. These data suggest that targeting the IL-8/AKT1 signaling pathway and DNMT1 may provide a potential therapeutic approach for blocking NPC metastasis.

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