Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation.
Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation.
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环肽 RA-V 抑制 YAP 激活诱导的器官增大和肿瘤发生
DOI：
10.3390/cancers10110449
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发表时间：
2018-11-16
期刊：
影响因子：
5.2
通讯作者：
Zhao B
中科院分区：
文献类型：
--
作者：
Ji X;Song L;Sheng L;Gao A;Zhao Y;Han S;Zhang Y;Zhu C;Zhao S;Wang Z;Xu B;Li L;Li J;Tan N;Zhao B
Hippo 通路在发育过程中限制器官大小，其失活在癌症中起着至关重要的作用。 Yes相关蛋白（YAP）及其具有PSD-95/Dlg/ZO-1（PDZ）结合基序（TAZ）的旁系同源转录共激活因子是Hippo通路的转录共激活因子和效应子，在Hippo通路失活后介导器官的异常增大和肿瘤生长。已证明YAP基因失活可能是抑制肿瘤发生的有效方法。为了鉴定 YAP 的药理学抑制剂，我们使用 YAP 特异性报告分析筛选了 52,683 种化合物的库。在此筛选中，我们将环肽 RA-V（脱氧布伐定）鉴定为 YAP 和 TAZ 的特异性抑制剂，但其他报告基因则不然。出乎意料的是，后来的实验表明，RA-V 抑制 YAP 靶基因的蛋白质水平，但不抑制 mRNA 水平。然而，RA-V 强烈阻断 Mst1/2 敲除引起的肝脏肿大。此外，RA-V不仅能抑制YAP激活诱导的肝脏肿瘤发生，还能诱导已形成肿瘤的消退。我们发现RA-V抑制去分化和增殖，同时诱导肝细胞凋亡。此外，RA-V 还诱导细胞凋亡并抑制微环境中巨噬细胞的增殖，这对于 YAP 诱导的肿瘤发生至关重要。因此，RA-V 是治疗涉及 YAP/TAZ 激活的癌症的候选药物。
The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation.
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