Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2

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. JohnsonLiang Zhu, Daming Gao, Lanfen Chen, Dawang Zhou

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)669-684.e7
JournalCancer Cell
Volume31
Issue number5
DOIs
StatePublished - May 8 2017

Keywords

  • Hippo
  • Skp2
  • Yap
  • genomic instability
  • p27
  • polyploidy
  • tumorigenesis

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Zhang, S., Chen, Q., Liu, Q., Li, Y., Sun, X., Hong, L., Ji, S., Liu, C., Geng, J., Zhang, W., Lu, Z., Yin, Z. Y., Zeng, Y., Lin, K. H., Wu, Q., Li, Q., Nakayama, K., Nakayama, K. I., Deng, X., ... Zhou, D. (2017). Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2. Cancer Cell, 31(5), 669-684.e7. https://doi.org/10.1016/j.ccell.2017.04.004