EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis.
EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis.
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DOI：
10.18632/oncotarget.14586
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发表时间：
2017-02-21
期刊：
影响因子：
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通讯作者：
Sakuragi N
中科院分区：
文献类型：
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作者：
Ihira K;Dong P;Xiong Y;Watari H;Konno Y;Hanley SJ;Noguchi M;Hirata N;Suizu F;Yamada T;Kudo M;Sakuragi N
EZH 2抑制和肿瘤抑制微RNA（miRNA）的再激活代表了有吸引力的抗癌治疗策略。我们发现，EZH 2抑制let 7 b和miR-361，两个可能的肿瘤抑制因子，抑制子宫内膜癌（EC）细胞增殖和侵袭，并废除癌症干细胞样特性。在EC细胞中，EZH 2诱导并与YY 1一起发挥作用以表观遗传抑制miR-361，其上调Twist，其是miR-361的直接靶点。用特异性EZH 2抑制剂GSK 343处理EC细胞，模拟siRNA介导的EZH 2敲低的作用，上调miR-361并下调Twist表达。联合应用GSK 343和5-AZA-2′-脱氧胞苷在体外协同抑制EC细胞增殖和侵袭，并减少EC细胞异种移植小鼠的肿瘤大小和重量。对24例原发性EC组织的定量实时PCR分析显示，let-7 b和miR-361水平较低与患者预后较差相关。这些结果在来自癌症基因组图谱的更大的EC患者数据集中得到了验证。我们的研究结果表明，EZH 2通过调节miR-361/Twist信号来驱动EC进展，并支持EZH 2抑制作为一种有前途的抗EC治疗策略。
EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2′-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.