title: EZH2 promotes angiogenesis through inhibition of miR-1/Endothelin-1 axis in nasopharyngeal carcinoma.
abstract: Emerging evidence clearly indicates that EZH2 plays a crucial role in tumor angiogenesis. However, the role of EZH2 in angiogenesis is still unknown in nasopharyngeal carcinoma (NPC). We here showed that the elevated EZH2 level was closely associated with an aggressive and poor prognostic phenotype, and was positively correlated with microvessel density (MVD) in NPC tissues. Functional studies showed that EZH2 upregulation promoted cell proliferation, migration and tubule formation of endothelial cells, and knockdown of EZH2 suppressed tumor growth, metastasis and angiogenesis in vivo. Mechanistic investigations revealed that EZH2 inhibited miR-1 transcription via promoter binding activity, leading to enhanced expression of Endothelin-1 (ET-1) which is suppressed by miR-1 targeting of ET-1 3'UTR. Furthermore, knockdown of EZH2 or overexpression of miR-1 exerted anti-angiogenic effect on NPC cells. More importantly, the neutralizing antibody against ET-1 significantly abrogated the pro-angiogenic effect of EZH2, and forced expression of ET-1 rescued the anti-angiogenic effect induced by EZH2 knockdown. In clinical specimens, ET-1 was widely overexpressed and associated with clinical stage and MVD. Taken together, our results identify a novel signaling pathway involved in NPC angiogenesis, and also suggest that EZH2-miR-1-ET-1 axis represents multiple potential therapeutic targets for NPC.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Fei-Peng
authors.initials: FP
authors.lastname: Zhao
authors.affiliation: Lab of Otolaryngology &Head and Neck tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zengliu
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Meng-Wen
authors.initials: MW
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital, Shantou University Medical College, Shantou, China.
authors.forename: Shao-Xiong
authors.initials: SX
authors.lastname: Lin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Bi-Jun
authors.initials: BJ
authors.lastname: Liang
authors.affiliation: School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China.
authors.forename: Bao
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wen-Dong
authors.initials: WD
authors.lastname: Tian
authors.affiliation: Department of Neurology, The Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Key Laboratory of malignant tumor gene regulation and target therapy of Guangdong Higher Education Institutes, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Biomedical Science, City University of Hong Kong, Hong Kong, China.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: He
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002642:Chick Embryo; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D055785:Gene Knockdown Techniques; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D020533:Angiogenesis Inhibitors; D019332:Endothelin-1; C544547:MIRN1 microRNA, human; D035683:MicroRNAs; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2