Zhang Shihao, Chen Qinghua, Liu Qingxu, Li Yuxi, Sun Xiufeng, Hong Lixin, Ji Suyuan, Liu Chengyan, Geng Jing, Zhang Weiji, Lu Zhonglei, Yin Zhen-Yu, Zeng Yuanyuan, Lin Kwang-Huei, Wu Qiao, Li Qiyuan, Nakayama Keiko, Nakayama Keiich I, Deng Xianming, Johnson Randy L, Zhu Liang, Gao Daming, Chen Lanfen, Zhou Dawang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Cancer Cell. 2017 May 8;31(5):669-684.e7. doi: 10.1016/j.ccell.2017.04.004.
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.
多倍体可导致非整倍体和肿瘤发生。在此，我们报告Hippo信号通路效应因子Yap通过Akt-Skp2轴促进二倍体-多倍体转化和多倍体细胞生长。Yap通过Akt信号强烈诱导乙酰转移酶p300介导的E3连接酶Skp2乙酰化。乙酰化的Skp2仅定位于细胞质中，这导致细胞周期蛋白依赖性激酶抑制剂p27过度积累，导致有丝分裂停滞并随后导致细胞多倍体化。此外，促凋亡因子FoxO1/3被乙酰化的Skp2过度降解，导致多倍体细胞分裂、基因组不稳定和肿瘤发生。重要的是，Akt或Skp2的缺失或失活消除了Hippo信号缺陷诱导的肝肿瘤发生，表明它们之间存在上位性相互作用。因此，我们得出结论，Hippo-Yap信号通路通过Skp2抑制细胞多倍体化和肿瘤发生。
