Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells.

S Hibino,H Saito,Y Saito,Y Kasai,A Otani,M Kimura,T Muramatsu

doi:10.1038/oncsis.2014.17

Abstract

Enhancer of zeste homolog 2 (EZH2) enhances tumorigenesis and is commonly overexpressed in several types of cancer. To investigate the anticancer effects of EZH2 inhibitors, microRNA (miRNA) expression profiles were examined in gastric and liver cancer cells treated with suberoylanilide hydroxamic acid (SAHA) and 3-deazaneplanocin A (DZNep). We confirmed that SAHA and DZNep suppressed EZH2 expression in AGS and HepG2 cells and inhibited their proliferation. The results of microarray analyses demonstrated that miR-1246 was commonly upregulated in cancer cells by treatment with SAHA and DZNep. MiR-302a and miR-4448 were markedly upregulated by treatment with SAHA and DZNep, respectively. DYRK1A, CDK2, BMI-1 and Girdin, which are targets of miR-1246, miR-302a and miR-4448, were suppressed by treatment with SAHA and DZNep, leading to apoptosis, cell cycle arrest and reduced migration of AGS and HepG2 cells. ChIP assay revealed that SAHA and DZNep inhibited the binding of EZH2 to the promoter regions of miR-1246, miR-302a and miR-4448. These findings suggest that EZH2 inhibitors such as SAHA and DZNep exert multiple anticancer effects through activation of tumor-suppressor miRNAs.

Highlights

Epigenetic silencing of tumor-suppressor genes in human cancer is mediated by aberrant DNA methylation and histone modification
suberoylanilide hydroxamic acid (SAHA) is widely accepted as an histone deacetylase (HDAC) inhibitor, it has been reported to suppress Enhancer of zeste homolog 2 (EZH2) expression in cancer cells and to exert an anticancer effect, indicating that SAHA functions as an EZH2 inhibitor.[5,6]
The numbers of AGS and HepG2 cells were significantly reduced 72 h after treatment with SAHA and deazaneplanocin A (DZNep). These findings suggest that both AGS and HepG2 cells are sensitive to SAHA and DZNep, and that these histone-modifying drugs inhibit EZN2 expression and the proliferative activity of cancer cells derived from the stomach and the liver

Summary

Introduction

Epigenetic silencing of tumor-suppressor genes in human cancer is mediated by aberrant DNA methylation and histone modification. The polycomb repressive complex 2 mediates epigenetic gene silencing by trimethylating histone H3 lysine 27 and is known to aberrantly silence tumor-suppressor genes in cancer. Epigenetic therapy with DNA methylation inhibitors and histone-modifying drugs has emerged as an effective approach for chemotherapy as well as chemoprevention of cancer. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) has been approved for patients with cutaneous T-cell lymphoma.[3] Recently, it was discovered that 3-deazaneplanocin A (DZNep) inhibits EZH2, which has H3K27 trimethylation activity.[4] SAHA is widely accepted as an HDAC inhibitor, it has been reported to suppress EZH2 expression in cancer cells and to exert an anticancer effect, indicating that SAHA functions as an EZH2 inhibitor.[5,6]

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Results

Conclusion