Hippo signaling dysfunction induces cancer cell addiction to YAP.
Hippo signaling dysfunction induces cancer cell addiction to YAP.
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DOI：
10.1038/s41388-018-0419-5
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发表时间：
2018-12
期刊：
影响因子：
8
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Han H;Yang B;Nakaoka HJ;Yang J;Zhao Y;Le Nguyen K;Bishara AT;Mandalia TK;Wang W
在过去的几十年里，Hippo已被确立为参与器官大小控制和癌症抑制的关键途径。Hippo信号传导的失调和其下游效应物雅普的过度活化经常与各种人类癌症相关。然而，这种雅普活化在癌症发展和治疗中的潜在意义尚未完全表征。在这项研究中，我们报道了Hippo信号转导缺陷可以导致癌细胞的YAP依赖性癌基因成瘾。通过临床化合物库筛选，我们鉴定了组蛋白脱乙酰酶（HDAC）抑制剂作为抑制雅普表达的推定抑制剂。重要的是，HDAC抑制剂特异性靶向其中雅普具有组成型活性的癌细胞的存活力和异种移植肿瘤生长。综上所述，我们的研究结果不仅建立了一个积极的YAP诱导癌基因成瘾的癌细胞，但也奠定了基础，开发靶向治疗与Hippo功能障碍和雅普激活的癌症。
Over the past decades, the Hippo has been established as a crucial pathway involved in organ size control and cancer suppression. Dysregulation of Hippo signaling and hyperactivation of its downstream effector YAP are frequently associated with various human cancers. However, the underlying significance of such YAP activation in cancer development and therapy has not been fully characterized. In this study, we reported that the Hippo signaling deficiency can lead to a YAP-dependent oncogene addiction for cancer cells. Through a clinical compound library screen, we identified histone deacetylase (HDAC) inhibitors as putative inhibitors to suppress YAP expression. Importantly, HDAC inhibitors specifically targeted the viability and xenograft tumor growth for the cancer cells in which YAP is constitutively active. Taken together, our results not only establish an active YAP-induced oncogene addiction in cancer cells, but also lay the foundation to develop targeted therapies for the cancers with Hippo dysfunction and YAP activation.
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