title: MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2.
abstract: Several microRNAs (miRNA) have been implicated in nasopharyngeal carcinoma (NPC), a highly invasive and metastatic cancer that is widely prevalent in southern China. In this study, we report that microRNA miR-26a is commonly downregulated in NPC specimens and NPC cell lines with important functional consequences. Ectopic expression of miR-26a dramatically suppressed cell proliferation and colony formation by inducing G(1)-phase cell-cycle arrest. We found that miR-26a strongly reduced the expression of EZH2 oncogene in NPC cells. Similar to the restoring miR-26 expression, EZH2 downregulation inhibited cell growth and cell-cycle progression, whereas EZH2 overexpression rescued the suppressive effect of miR-26a. Mechanistic investigations revealed that miR-26a suppressed the expression of c-myc, the cyclin D3 and E2, and the cyclin-dependent kinase CDK4 and CDK6 while enhancing the expression of CDK inhibitors p14(ARF) and p21(CIP1) in an EZH2-dependent manner. Interestingly, cyclin D2 was regulated by miR-26a but not by EZH2, revealing cyclin D2 as another direct yet mechanistically distinct target of miR-26a. In clinical specimens, EZH2 was widely overexpressed and its mRNA levels were inversely correlated with miR-26a expression. Taken together, our results indicate that miR-26a functions as a growth-suppressive miRNA in NPC, and that its suppressive effects are mediated chiefly by repressing EZH2 expression.
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.forename: Ming-Liang
authors.initials: ML
authors.lastname: He
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiong
authors.initials: X
authors.lastname: Liu
authors.forename: Qi
authors.initials: Q
authors.lastname: Dong
authors.forename: Yang-Chao
authors.initials: YC
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.forename: Kai-Tai
authors.initials: KT
authors.lastname: Yao
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D009303:Nasopharyngeal Neoplasms / Q000473:pathology*; D063151:Polycomb Repressive Complex 2; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D035683:MicroRNAs; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2