title: IL-8 suppresses E-cadherin expression in nasopharyngeal carcinoma cells by enhancing E-cadherin promoter DNA methylation.
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.
authors.affiliation: Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. China.
authors.forename: Rui-Li
authors.initials: RL
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Meng-Yao
authors.initials: MY
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Bi-Jun
authors.initials: BJ
authors.lastname: Huang
authors.affiliation: Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. China.
authors.forename: Hua-Rong
authors.initials: HR
authors.lastname: Zhao
authors.affiliation: Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. China.
authors.forename: Yong-Xing
authors.initials: YX
authors.lastname: Bao
authors.affiliation: 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.
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Qian
mesh_terms: D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002277:Carcinoma; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D015820:Cadherins; D016209:Interleukin-8; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt