TY - JOUR
T1 - Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2
AU - Zhang, Shihao
AU - Chen, Qinghua
AU - Liu, Qingxu
AU - Li, Yuxi
AU - Sun, Xiufeng
AU - Hong, Lixin
AU - Ji, Suyuan
AU - Liu, Chengyan
AU - Geng, Jing
AU - Zhang, Weiji
AU - Lu, Zhonglei
AU - Yin, Zhen Yu
AU - Zeng, Yuanyuan
AU - Lin, Kwang Huei
AU - Wu, Qiao
AU - Li, Qiyuan
AU - Nakayama, Keiko
AU - Nakayama, Keiich I.
AU - Deng, Xianming
AU - Johnson, Randy L.
AU - Zhu, Liang
AU - Gao, Daming
AU - Chen, Lanfen
AU - Zhou, Dawang
N1 - Funding Information:
The Yap (S127A) transgenic mice were kindly provided by Dr. Fernando Camargo from Harvard Medical School, Boston, MA. D.Z. and L.C. were supported by the National Natural Science Foundation of China (31625010, U1505224, and J1310027 to D.Z.; 81422018, U1405225, and 81372617 to L.C.; 81472229 to L.H.), the National Basic Research Program (973) of China (2015CB910502 to L.C.), the Fundamental Research Funds for the Central Universities of China-Xiamen University (20720140551 to L.C. and 2013121034 and 20720140537 to D.Z.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2017 Elsevier Inc.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/5/8
Y1 - 2017/5/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccell.2017.04.004
DO - 10.1016/j.ccell.2017.04.004
M3 - Article
C2 - 28486106
AN - SCOPUS:85019059302
VL - 31
SP - 669-684.e7
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 5
ER -