State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, 271018, Tai'an, China.
Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, 519000, Zhuhai, China.
Nat Commun. 2019 Jan 24;10(1):411. doi: 10.1038/s41467-019-08334-7.
The Hippo pathway plays an important role in organ development and adult tissue homeostasis, and its deregulation has been implicated in many cancers. The Hippo signaling relies on a core kinase cascade culminating in phosphorylation of the transcription coactivator Yorkie (Yki). Although Yki is the key effector of Hippo pathway, the regulation of its protein stability is still unclear. Here, we show that Hippo pathway attenuates the binding of a ubiquitin-specific protease Usp7 to Yki, which regulates Hippo signaling through deubiquitinating Yki. Furthermore, the mammalian homolog of Usp7, HAUSP plays a conserved role in regulating Hippo pathway by modulating Yap ubiquitination and degradation. Finally, we find that the expression of HAUSP is positively correlated with that of Yap, both showing upregulated levels in clinical hepatocellular carcinoma (HCC) specimens. In summary, our findings demonstrate that Yki/Yap is stabilized by Usp7/HAUSP, and provide HAUSP as a potential therapeutic target for HCC.
Hippo 通路在器官发育和成人组织稳态中发挥着重要作用，其失调与许多癌症有关。Hippo 信号依赖于一个核心激酶级联反应，最终导致转录共激活因子 Yorkie（Yki）的磷酸化。尽管 Yki 是 Hippo 通路的关键效应物，但它的蛋白质稳定性的调节仍不清楚。在这里，我们表明 Hippo 通路减弱了泛素特异性蛋白酶 Usp7 与 Yki 的结合，从而通过去泛素化 Yki 来调节 Hippo 信号。此外，Usp7 的哺乳动物同源物 HAUSP 通过调节 Yap 的泛素化和降解在调节 Hippo 通路中发挥保守作用。最后，我们发现 HAUSP 的表达与 yap 的表达呈正相关，两者在临床肝细胞癌（HCC）标本中均表现出上调水平。总之，我们的研究结果表明，Yki/Yap 被 Usp7/HAUSP 稳定，为 HCC 提供了一个潜在的治疗靶点。
