Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells.
Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells.
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Zeste同源物2（EZH2）增强子的抑制剂激活人类癌细胞中的肿瘤抑制剂。
DOI：
10.1038/oncsis.2014.17
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发表时间：
2014-05-26
期刊：
影响因子：
6.2
通讯作者：
Saito, H.
中科院分区：
文献类型：
--
作者：
Hibino, S.;Saito, Y.;Muramatsu, T.;Otani, A.;Kasai, Y.;Kimura, M.;Saito, H.
ZAST同源增强子2(EZH2)促进肿瘤的发生，在几种类型的癌症中通常过度表达。为探讨EZH2抑制剂的抗癌作用，检测了Suberoylanilide异羟肟酸(SAHA)和3-去氮杂环素A(DZNep)处理的胃癌细胞和肝癌细胞的microRNA(MiRNA)的表达谱。我们证实，SAHA和DZNep抑制AGS和HepG2细胞中EZH2的表达，并抑制其增殖。基因芯片分析结果表明，SAHA和DZNep处理后，miR-1246在癌细胞中的表达普遍上调。SAHA和DZNep分别可显著上调MIR-302a和miR-4448的表达。SAHA和DZNep可抑制miR-1246、miR-302a和miR-4448的靶点DYRK1A、CDK2、Bmi-1和Girdin，导致AGS和HepG2细胞凋亡、细胞周期停滞和迁移减少。芯片分析显示，SAHA和DZNep抑制EZH2与miR-1246、miR-302a和miR-4448启动子区域的结合。这些发现表明，EZH2抑制剂如SAHA和DZNep通过激活肿瘤抑制因子miRNAs发挥多种抗癌作用。
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.
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影响因子：
8
作者：
Saito, Y.;Suzuki, H.;Hibi, T.
通讯作者：
Hibi, T.
影响因子：
3.7
作者：
Saito Y;Saito H
通讯作者：
Saito H
影响因子：
50.3
作者：
Chang CJ;Yang JY;Xia W;Chen CT;Xie X;Chao CH;Woodward WA;Hsu JM;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
11.2
作者：
Chen, Hsin-Yi;Lin, Yu-Min;Chen, Ruey-Hwa
通讯作者：
Chen, Ruey-Hwa
影响因子：
4.5
作者：
Lin, Shi-Lung;Chang, Donald C.;Ying, Shao-Yao
通讯作者：
Ying, Shao-Yao