EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma.
EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma.
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EZH2介导的GSK-3β和TP53抑制促进宫颈癌中Wnt/β-连环蛋白信号依赖性细胞扩增
DOI：
10.18632/oncotarget.8741
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发表时间：
2016-06-14
期刊：
影响因子：
--
通讯作者：
Yang WT
中科院分区：
文献类型：
--
作者：
Chen Q;Zheng PS;Yang WT
zeste homolog 2的增强子（Enhancer of zeste homolog 2, EZH2）是Polycomb抑制复合体2 （PRC2）的催化核心成分，通过组蛋白H3赖氨酸27三甲基化（H3K27me3）刺激靶基因的沉默。最近的研究表明，EZH2参与了各种人类癌症的发生和发展。然而，EZH2促进宫颈癌的确切机制在很大程度上是未知的。我们发现EZH2的表达在宫颈癌的发展过程中逐渐增加。我们利用crispr - cas9介导的基因编辑技术和shRNA在HeLa和SiHa细胞中上调或下调EZH2的表达，发现EZH2的表达与体外细胞增殖和体内肿瘤形成之间存在显著的正相关。进一步研究表明，EZH2蛋白显著加速了细胞周期从G0/G1期向S期的转变。TOP/ TOP - flash报告基因检测结果显示，EZH2显著激活Wnt/β-catenin信号通路，上调Wnt/β-catenin通路靶基因，包括β-catenin、cyclin D1、c-myc。此外，双荧光素酶报告基因和染色质免疫沉淀（ChIP）实验证实，EZH2通过与GSK-3β和TP53基因启动子中的基序物理相互作用，抑制糖原合成酶激酶3β (GSK-3β)和TP53的表达。此外，阻断Wnt/β-catenin通路可显著抑制细胞增殖，激活Wnt/β-catenin通路可显著增强EZH2诱导的细胞增殖。综上所述，我们的数据表明EZH2通过GSK-3β和TP53的表观遗传沉默激活Wnt/β-catenin通路，从而促进宫颈癌细胞增殖和肿瘤形成。
Enhancer of zeste homolog 2 (EZH2), a catalytic core component of the Polycomb repressive complex 2 (PRC2), stimulates the silencing of target genes through histone H3 lysine 27 trimethylation (H3K27me3). Recent findings have indicated EZH2 is involved in the development and progression of various human cancers. However, the exact mechanism of EZH2 in the promotion of cervical cancer is largely unknown. Here, we show that EZH2 expression gradually increases during the progression of cervical cancer. We identified a significant positive correlation between EZH2 expression and cell proliferation in vitro and tumor formation in vivo by the up-regulation or down-regulation of EZH2 using CRISPR-Cas9-mediated gene editing technology and shRNA in HeLa and SiHa cells. Further investigation indicated that EZH2 protein significantly accelerated the cell cycle transition from the G0/G1 to S phase. TOP/FOP-Flash reporter assay revealed that EZH2 significantly activated Wnt/β-catenin signaling and the target genes of Wnt/β-catenin pathway were up-regulated, including β-catenin, cyclin D1, and c-myc. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays confirmed that EZH2 inhibited the expression of glycogen synthase kinase-3β (GSK-3β) and TP53 through physically interacting with motifs in the promoters of the GSK-3β and TP53 genes. Additionally, blockage of the Wnt/β-catenin pathway resulted in significant inhibition of cell proliferation, and activation of the Wnt/β-catenin pathway resulted in significant enhancement of cell proliferation, as induced by EZH2. Taken together, our data demonstrate that EZH2 promotes cell proliferation and tumor formation in cervical cancer through activating the Wnt/β-catenin pathway by epigenetic silencing via GSK-3β and TP53.
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影响因子：
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作者：
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