title: EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin.
abstract: The enhancer of zeste homolog 2 (EZH2) is upregulated and has an oncogenic role in several types of human cancer. However, the abnormalities of EZH2 and its underlying mechanisms in the pathogenesis of nasopharyngeal carcinoma (NPC) remain unknown. In this study, we found that high expression of EZH2 in NPC was associated closely with an aggressive and/or poor prognostic phenotype (P<0.05). In NPC cell lines, knockdown of EZH2 by short hairpin RNA was sufficient to inhibit cell invasiveness/metastasis both in vitro and in vivo, whereas ectopic overexpression of EZH2 supported NPC cell invasive capacity with a decreased expression of E-cadherin. In addition, ablation of endogenous Snail in NPC cells virtually totally prevented the repressive activity of EZH2 to E-cadherin, indicating that Snail might be a predominant mediator of EZH2 to suppress E-cadherin. Furthermore, co-immunoprecipitation (IP), chromatin IP and luciferase reporter assays demonstrated that in NPC cells, (1) EZH2 interacted with HDAC1/HDAC2 and Snail to form a repressive complex; (2) these components interact in a linear fashion, not in a triangular fashion, that is, HDAC1 or HDAC2 bridge the interaction between EZH2 and Snail; and (3) the EZH2/HDAC1/2/Snail complex could closely bind to the E-cadherin promoter by Snail, but not YY1, to repress E-cadherin. The data provided in this report suggest a critical role of EZH2 in the control of cell invasion and/or metastasis by forming a co-repressor complex with HDAC1/HDAC2/Snail to repress E-cadherin, an activity that might be responsible, at least in part, for the development and/or progression of human NPCs.
authors.affiliation: The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Z-T
authors.initials: ZT
authors.lastname: Tong
authors.forename: M-Y
authors.initials: MY
authors.lastname: Cai
authors.forename: X-G
authors.initials: XG
authors.lastname: Wang
authors.forename: L-L
authors.initials: LL
authors.lastname: Kong
authors.forename: S-J
authors.initials: SJ
authors.lastname: Mai
authors.forename: Y-H
authors.initials: YH
authors.lastname: Liu
authors.forename: H-B
authors.initials: HB
authors.lastname: Zhang
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Liao
authors.forename: F
authors.initials: F
authors.lastname: Zheng
authors.forename: W
authors.initials: W
authors.lastname: Zhu
authors.forename: T-H
authors.initials: TH
authors.lastname: Liu
authors.forename: X-W
authors.initials: XW
authors.lastname: Bian
authors.forename: X-Y
authors.initials: XY
authors.lastname: Guan
authors.forename: M C
authors.initials: MC
authors.lastname: Lin
authors.forename: M-S
authors.initials: MS
authors.lastname: Zeng
authors.forename: Y-X
authors.initials: YX
authors.lastname: Zeng
authors.forename: H-F
authors.initials: HF
authors.lastname: Kung
authors.forename: D
authors.initials: D
authors.lastname: Xie
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2