EZH2-Mediated Downregulation of the Tumor Suppressor DAB2IP Maintains Ovarian Cancer Stem Cells.
EZH2-Mediated Downregulation of the Tumor Suppressor DAB2IP Maintains Ovarian Cancer Stem Cells.
复制标题
EZH2介导的肿瘤抑制因子DAB 2IP的下调维持卵巢癌干细胞。
DOI：
10.1158/0008-5472.can-20-0458
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发表时间：
2020-10-15
期刊：
影响因子：
11.2
通讯作者：
Nephew KP
中科院分区：
文献类型：
--
作者：
Zong X;Wang W;Ozes A;Fang F;Sandusky GE;Nephew KP
大多数被诊断为上皮性卵巢癌(OC)的女性最终会复发，并迅速演变为化疗耐药疾病。卵巢癌干细胞(OCSC)在治疗结束时的持久性可能是耐药肿瘤出现的原因。在这项研究中，我们证明在口腔鳞癌中，肿瘤抑制因子失活的同源蛋白2相互作用蛋白(DAB2IP)被EZH2介导的DAB2IP启动子的H3K27三甲基化所沉默。CRISPR/Cas9介导的DAB2IP在上皮性OC细胞系中的缺失上调了与干性相关的基因的表达，并诱导了非CSC向CSC的转化，而DAB2IP的强制表达抑制了CSC的特性。转录分析表明，DAB2IP在OC中的过表达显著改变了与茎干相关的基因，生物信息学分析表明，WNT信号是介导DAB2IP抑制CSC效应的主要途径。具体地说，DAB2IP通过下调重要的茎干诱导因子WNT5B来抑制WNT信号传导。反相蛋白质阵列进一步证明了非规范的WNT信号通过C-Jun被激活，作为WNT5B的下游靶点，WNT5B被抑制C-Jun激活的重要调节因子RAC1所阻断。联合应用EZH2抑制剂GSK126和RAC1抑制剂NSC23766可在体外抑制OCSC的存活，在体内抑制肿瘤生长并增加对铂的敏感性。总体而言，这些数据表明，DAB2IP通过抑制WNT5B诱导的C-jun的激活来抑制肿瘤干细胞的表型，并可以被OCSC中的EZH2表观遗传沉默。因此，以EZH2/DAB2IP/C-Jun轴为靶点是预防OC复发的一种有前景的策略，并具有临床翻译的潜力。
The majority of women diagnosed with epithelial ovarian cancer (OC) eventually develop recurrence which rapidly evolves into chemoresistant disease. Persistence of ovarian cancer stem cells (OCSC) at the end of therapy may be responsible for emergence of resistant tumors. In this study, we demonstrate that in OCSC, the tumor suppressor Disabled Homolog 2-Interacting Protein (DAB2IP) is silenced by EZH2-mediated H3K27 trimethylation of the DAB2IP promoter. CRISPR/Cas9-mediated deletion of DAB2IP in epithelial OC cell lines upregulated expression of stemness-related genes and induced conversion of non-CSC to CSC, while enforced expression of DAB2IP suppressed CSC properties. Transcriptomic analysis showed that overexpression of DAB2IP in OC significantly altered stemness-associated genes and bioinformatic analysis revealed WNT signaling as a dominant pathway mediating the CSC inhibitory effect of DAB2IP. Specifically, DAB2IP inhibited WNT signaling via downregulation of WNT5B, an important stemness inducer. Reverse Phase Protein Array further demonstrated activation of non-canonical WNT signaling via C-JUN as a downstream target of WNT5B, which was blocked by inhibiting RAC1, a prominent regulator of C-JUN activation. Co-administration of EZH2 inhibitor GSK126 and RAC1 inhibitor NSC23766 suppressed OCSC survival in vitro and inhibited tumor growth and increased platinum sensitivity in vivo. Overall, these data establish that DAB2IP suppresses the cancer stem cell phenotype via inhibition of WNT5B-induced activation of C-JUN and can be epigenetically silenced by EZH2 in OCSC. Targeting the EZH2/DAB2IP/C-JUN axis therefore presents a promising strategy to prevent OC recurrence and has potential for clinical translation.