EZH2 activates CHK1 signaling to promote ovarian cancer chemoresistance by maintaining the properties of cancer stem cells.
EZH2 activates CHK1 signaling to promote ovarian cancer chemoresistance by maintaining the properties of cancer stem cells.
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EZH2 激活 CHK1 信号传导，通过维持癌症干细胞的特性来促进卵巢癌化疗耐药
作者：
Wen Y;Hou Y;Yi X;Sun S;Guo J;He X;Li T;Cai J;Wang Z
研究背景：卵巢癌是妇科常见的恶性肿瘤。卵巢癌干细胞（OCSC）有助于抵抗化疗。polycomb group protein enhancer of zeste homolog 2（EZH 2）在维持CSC中起关键作用。在此，我们的目的是研究EZH 2调节CSC导致卵巢癌化疗耐药和预后不良的具体机制。方法：采用裸鼠移植瘤模型，获得富含OCSC的细胞系SK-3rd细胞。使用CRISPR和Cas9内切核酸酶系统来建立EZH 2敲除的SK-3rd卵巢癌细胞系。利用高通量PCR芯片和生物信息学方法筛选CSC干性相关的EZH 2靶基因。进行荧光素酶报告基因测定和染色质免疫沉淀测定以鉴定EZH 2对CHK 1的激活。我们评估了EZH 2/CHK 1表达与卵巢癌患者化疗耐药性和预后之间的关系。结果：EZH 2在维持卵巢CSC的干性和化疗抵抗中起关键作用。CHK 1是参与CSC干性的EZH 2靶标。卵巢CSC中EZH 2的敲低降低了CHK 1的表达，而CHK 1的过表达足以逆转对EZH 2抑制引起的球体形成和化疗耐药性的抑制作用。此外，EZH 2也被证明通过与上皮性卵巢癌细胞中的CHK 1启动子结合，在激活而不是抑制CHK 1信号传导中发挥独特作用。最后，在临床样本中，EZH 2和CHK 1水平高的卵巢癌患者不仅对铂类药物耐药，而且预后较差。结论：我们的数据揭示了EZH 2水平，CHK 1信号激活和卵巢CSC之间先前未识别的功能和机制联系，并提供了EZH 2促进卵巢癌化疗耐药性和复发的有力证据。
Background: Ovarian cancer is a fatal malignant gynecological tumor. Ovarian cancer stem cells (OCSCs) contribute to resistance to chemotherapy. The polycomb group protein enhancer of zeste homolog 2 (EZH2) plays a key role in maintaining CSCs. Here, we aimed to investigate the specific mechanism by which EZH2 regulates CSCs to result in chemoresistance and poor prognosis of ovarian cancer. Methods: We used a nude mouse model to obtain a cell line enriched for OCSCs, named SK-3rd cells. The CRISPR and Cas9 endonuclease system was used to establish an EZH2-knockout SK-3rd ovarian cancer cell line. High-throughput PCR array and bioinformatics methods were used to screen the EZH2 target involved in CSC stemness. A luciferase reporter assay and chromatin immunoprecipitation assay were performed to identify activation of CHK1 by EZH2. We evaluated associations between EZH2/CHK1 expression and the chemoresistance and prognosis of ovarian cancer patients. Results: EZH2 plays a critical role in maintaining ovarian CSC stemness and chemo-resistance. CHK1 is an EZH2 target involved in CSC stemness. Knockdown of EZH2 in ovarian CSCs decreased CHK1 expression, while CHK1 overexpression was sufficient to reverse the inhibitory effect on spheroid formation and chemoresistance caused by repression of EZH2. In addition, EZH2 was also shown to play a unique role in activating rather than repressing CHK1 signaling through binding to the CHK1 promoter in epithelial ovarian cancer cells. Finally, in clinical samples, ovarian cancer patients with high levels of EZH2 and CHK1 not only were more resistant to platinum but also had a poorer prognosis. Conclusions: Our data revealed a previously unidentified functional and mechanistic link between EZH2 levels, CHK1 signaling activation, and ovarian CSCs and provided strong evidence that EZH2 promotes ovarian cancer chemoresistance and recurrence.
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DOI：
10.1038/nrclinonc.2013.5
发表时间：
2013-04
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
11.2
作者：
Adorno-Cruz V;Kibria G;Liu X;Doherty M;Junk DJ;Guan D;Hubert C;Venere M;Mulkearns-Hubert E;Sinyuk M;Alvarado A;Caplan AI;Rich J;Gerson SL;Lathia J;Liu H
通讯作者：
Liu H