Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2

Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Shihao Zhang, Qinghua Chen, Qingxu Liu, Yuxi Li, Xiufeng Sun, Lixin Hong, Suyuan Ji, Chengyan Liu, Jing Geng, Weiji Zhang, Zhonglei Lu, Zhen-Yu Yin, Yuanyuan Zeng, Kwang-Huei Lin, Qiao Wu, Qiyuan Li, Keiko Nakayama, Keiich I. Nakayama, Xianming Deng, Randy L. Johnson, Liang Zhu, Daming Gao, Lanfen Chen, Dawang Zhou
Polyploidy can lead to aneuploidy and tumorigenesis. Here, we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis. Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling. Acetylated Skp2 is exclusively localized to the cytosol, which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27, leading to mitotic arrest and subsequently cell polyploidy. In addition, the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2, resulting in polyploid cell division, genomic instability, and oncogenesis. Importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.

Graphical abstract

Teaser

Zhang et al. show that Yap promotes polyploidy and polyploid cell growth via Akt signaling and p300-mediated acetylation of Skp2, which causes Skp2 cytosolic retention and differential regulation of p27 and FoxO1/3 stabilities. Dysregulated Hippo-Yap-Skp2 axis is associated with human hepatocellular carcinomas.


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