Epigenetic Silencing of miR-9 Promotes Migration and Invasion by EZH2 in Glioblastoma Cells.

Yi-Chung Chien,Han-Chung Lee,Yung-Luen Yu,Jia-Ni Chen,Ya-Huey Chen,Ruey-Hwang Chou

doi:10.3390/cancers12071781

Yi-Chung Chien, Han-Chung Lee + Show 4 more

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https://doi.org/10.3390/cancers12071781

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Abstract

Glioblastoma (GBM) is the most common primary brain tumor in adults. Tumor invasion is the major reason for treatment failure and poor prognosis in GBM. Inhibiting migration and invasion has become an important therapeutic strategy for GBM treatment. Enhancer of zeste homolog 2 (EZH2) and C-X-C motif chemokine receptor 4 (CXCR4) have been determined to have important roles in the occurrence and development of tumors, but the specific relationship between EZH2 and CXCR4 expression in GBM is less well characterized. In this study, we report that EZH2 and CXCR4 were overexpressed in glioma patients. Furthermore, elevated EZH2 and CXCR4 were correlated with shorter disease-free survival. In three human GBM cell lines, EZH2 modulated the expression of miR-9, which directly targeted the oncogenic signaling of CXCR4 in GBM. The ectopic expression of miR-9 dramatically inhibited the migratory capacity of GBM cells in vitro. Taken together, our results indicate that miR-9, functioning as a tumor-suppressive miRNA in GBM, is suppressed through epigenetic silencing by EZH2. Thus, miR-9 may be an attractive target for therapeutic intervention in GBM.

Highlights

Glioblastoma (GBM) remains among the most devastating cancers, with a median survival of less than 15 months and virtually no survival beyond 5 years [1]
We evaluated the association between the Enhancer of zeste homolog 2 (EZH2) mRNA level and clinical information or the CXCR4
The results revealed that GBM patients with high EZH2 and CXCR4 expression compared to normal people had significantly shorter disease-free survival than those with low EZH2 and CXCR4 expression (Figure 1a,b)

Summary

Introduction

Glioblastoma (GBM) remains among the most devastating cancers, with a median survival of less than 15 months and virtually no survival beyond 5 years [1]. EZH2, SUZ12 polycomb repressive complex 2 subunit (SUZ12), and embryonic ectoderm development (EED); PRC2 functions as a transcriptional repressor and plays an important role in coordinating gene. In GBM, the cancer-specific concordant hyper-methylation of the CpG islands suppresses the promoters of hundreds of genes, giving rise to the “glioma-CpG island methylator phenotype (G-CIMP)” [15]. It had been reported that high levels of EZH2 expression are associated with the invasion and metastasis of malignant tumors, such as breast cancers and non-small cell lung cancers [13,16]. Some reports have described that H3K27me by EZH2 is not always associated with promoter DNA methylation, which silences EZH2 target genes [17,18,19,20]

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