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 Johnson; Liang Zhu; Daming Gao; Lanfen Chen; Dawang Zhou

doi:10.1016/j.ccell.2017.04.004

Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2

Cancer Cell. 2017 May 8;31(5):669-684.e7. doi: 10.1016/j.ccell.2017.04.004.

Authors

Shihao Zhang¹, Qinghua Chen¹, Qingxu Liu¹, Yuxi Li¹, Xiufeng Sun¹, Lixin Hong¹, Suyuan Ji¹, Chengyan Liu¹, Jing Geng¹, Weiji Zhang¹, Zhonglei Lu², Zhen-Yu Yin³, Yuanyuan Zeng⁴, Kwang-Huei Lin⁵, Qiao Wu¹, Qiyuan Li⁴, Keiko Nakayama⁶, Keiich I Nakayama⁷, Xianming Deng¹, Randy L Johnson⁸, Liang Zhu², Daming Gao⁹, Lanfen Chen¹⁰, Dawang Zhou¹¹

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
² Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
³ Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China.
⁴ Department of Translational Medicine, Medical College of Xiamen University, Xiamen, Fujian 361102, China.
⁵ Department of Biochemistry, College of Medicine, Chang Gung University, Liver Research Center, Chang Gung Memorial Hospital, TaoYuan 333, Taiwan, ROC.
⁶ Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
⁷ Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
⁸ Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Key Laboratory of System Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
¹⁰ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: [email protected].
¹¹ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: [email protected].

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.

Keywords: Hippo; Skp2; Yap; genomic instability; p27; polyploidy; tumorigenesis.

MeSH terms

Acetylation
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Carcinoma, Hepatocellular / enzymology*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / pathology
Cell Cycle Proteins
Cell Proliferation*
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Cyclin-Dependent Kinase Inhibitor p27 / genetics
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Cytosol / enzymology
Epistasis, Genetic
Female
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Hep G2 Cells
Hippo Signaling Pathway
Humans
Liver Neoplasms / enzymology*
Liver Neoplasms / genetics
Liver Neoplasms / pathology
Mice
Mice, Transgenic
Phenotype
Phosphoproteins / genetics
Phosphoproteins / metabolism
Ploidies*
Pregnancy
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Protein Stability
Proteolysis
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
S-Phase Kinase-Associated Proteins / genetics
S-Phase Kinase-Associated Proteins / metabolism*
Signal Transduction
Time Factors
Transcription Factors
Transfection
YAP-Signaling Proteins
p300-CBP Transcription Factors / metabolism

Substances

Adaptor Proteins, Signal Transducing
CDKN1B protein, human
Cdkn1b protein, mouse
Cell Cycle Proteins
Forkhead Transcription Factors
Phosphoproteins
S-Phase Kinase-Associated Proteins
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
Yap1 protein, mouse
Cyclin-Dependent Kinase Inhibitor p27
p300-CBP Transcription Factors
p300-CBP-associated factor
Akt1 protein, mouse
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt

Abstract

MeSH terms

Substances

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