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

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

Department of Molecular and Cellular Biology

Research output: Contribution to journal › Article

54 Citations (Scopus)

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 language	English
Pages (from-to)	669-684.e7
Journal	Cancer Cell
Volume	31
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2017.04.004
Publication status	Published - May 8 2017

All Science Journal Classification (ASJC) codes

Oncology
Cell Biology
Cancer Research

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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

Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2. / 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.

In: Cancer Cell, Vol. 31, No. 5, 08.05.2017, p. 669-684.e7.

Research output: Contribution to journal › Article

Zhang, S, Chen, Q, Liu, Q, Li, Y, Sun, X, Hong, L, Ji, S, Liu, C, Geng, J, Zhang, W, Lu, Z, Yin, ZY, Zeng, Y, Lin, KH, Wu, Q, Li, Q, Nakayama, K, Nakayama, KI, Deng, X, Johnson, RL, Zhu, L, Gao, D, Chen, L & Zhou, D 2017, 'Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2', Cancer Cell, vol. 31, no. 5, pp. 669-684.e7. https://doi.org/10.1016/j.ccell.2017.04.004

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. / Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2. In: Cancer Cell. 2017 ; Vol. 31, No. 5. pp. 669-684.e7.

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title = "Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2",

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.",

author = "Shihao Zhang and Qinghua Chen and Qingxu Liu and Yuxi Li and Xiufeng Sun and Lixin Hong and Suyuan Ji and Chengyan Liu and Jing Geng and Weiji Zhang and Zhonglei Lu and Yin, {Zhen Yu} and Yuanyuan Zeng and Lin, {Kwang Huei} and Qiao Wu and Qiyuan Li and Keiko Nakayama and Nakayama, {Keiich I.} and Xianming Deng and Johnson, {Randy L.} and Liang Zhu and Daming Gao and Lanfen Chen and Dawang Zhou",

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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

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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