Ji Xinyan, Song Lihua, Sheng Li, Gao Anhui, Zhao Yang, Han Shixun, Zhang Yuchao, Zhu Chu, Zhao Simeng, Wang Zhe, Xu Bohan, Li Li, Li Jia, Tan Ninghua, Zhao Bin
MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
School of Traditional Chinese Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
Cancers (Basel). 2018 Nov 16;10(11):449. doi: 10.3390/cancers10110449.
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 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.
河马通路在发育过程中限制器官大小，其失活在癌症中起关键作用。Yes相关蛋白（YAP）及其旁系同源物具有与PSD-95/Dlg/ZO-1（PDZ）结合基序的转录共激活因子（TAZ）是河马通路的转录共激活因子和效应器，在河马通路失活时介导器官异常增大和肿瘤生长。已经证明YAP的基因失活可能是抑制肿瘤发生的有效方法。为了鉴定YAP的药理抑制剂，我们使用YAP特异性报告基因检测筛选了一个包含52683种化合物的文库。在这个筛选中，我们鉴定出环肽RA-V（脱氧布瓦定）是YAP和TAZ的特异性抑制剂，但不是其他报告基因的抑制剂。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而不是mRNA水平。尽管如此，RA-V强烈阻断由敲除诱导的肝脏肿大。此外，RA-V不仅抑制由YAP激活诱导的肝脏肿瘤发生，还诱导已建立肿瘤的消退。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还诱导微环境中巨噬细胞的凋亡并抑制其增殖，而巨噬细胞对于YAP诱导的肿瘤发生至关重要。因此，RA-V是涉及YAP/TAZ激活的癌症的候选药物。
