Abstract
Recent data have been shown that EZH2 is a critical oncogene via the repression of tumor suppressor genes in human cancers. In our study, we performed a genome-wide miRNA screen with a bioinformatics analysis to identify EZH2 specific miRNAs. Of these miRNAs, miR-524-5p and miR-324-5p were decreased in glioma tissues, and confered poor prognosis for glioma patients. Upregulation of miR-524-5p and miR-324-5p reduced glioma cell proliferation and increased temozolomide (TMZ) chemosensitivity by targeting EZH2. Importantly, the effection of miR-524-5p and miR-324-5p on cell proliferation and TMZ chemosensitivity in glioma were reversed by expression of EZH2 cDNA. Further, miR-524-5p and miR-324-5p overexpression suppressed glioma growth and prolonged survival in an intracranial xenograft model. Multivariate Cox regression analysis revealed that miR-524-5p was an independent prognostic factor in gliobalstoma patients. Taken together, these data indicate that miRNA-driven EZH2 repression may provide evidence of the molecular mechanism for gliomagenesis and the novel therapeutic targets for glioma.
Highlights
The methyltransferase enhancer of zeste homolog 2 (EZH2), is the core catalytic element of polycomb repressive complex 2 (PRC2), and plays an important role in the regulation of cancer initiation, progression, invasion, and drug resistance
Pearson correlation was performed to analyze the relationships of EZH2 and all miRNA values using matlab software. 57 positively and 71 negatively correlated miRNAs with EZH2 expression were detected
The miRNAs with negatively significant correlation with EZH2 level were considered as EZH2 specific miRNA signature
Summary
The methyltransferase enhancer of zeste homolog 2 (EZH2), is the core catalytic element of polycomb repressive complex 2 (PRC2), and plays an important role in the regulation of cancer initiation, progression, invasion, and drug resistance. Associations have been reported between EZH2 overexpression and poor prognosis in esophageal cancers [8], breast cancers [9], renal cell carcinomas [10] and childhood intracranial ependymoma [11]. Few studies of systematic mining EZH2 specific miRNA signature in human cancers have been reported. In this manuscript, we identified EZH2 specific miRNAs using integrated analysis of miRNA and mRNA arrays. Of these miRNAs, miR-524-5p and miR-324-5p confered poor prognosis for glioma patients and inhibited glioma cell proliferation by targeting EZH2
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