Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis

Dazhi Xu; Chien Feng Li; Xian Zhang; Zhaohui Gong; Chia Hsin Chan; Szu Wei Lee; Guoxiang Jin; Abdol Hossein Rezaeian; Fei Han; Jing Wang; Wei Lei Yang; Zi Zhen Feng; Wei Chen; Ching Yuan Wu; Ying Jan Wang; Lu Ping Chow; Xiao Feng Zhu; Yi Xin Zeng; Hui Kuan Lin

doi:10.1038/ncomms7641

Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis

Dazhi Xu, Chien Feng Li, Xian Zhang, Zhaohui Gong, Chia Hsin Chan, Szu Wei Lee, Guoxiang Jin, Abdol Hossein Rezaeian, Fei Han, Jing Wang, Wei Lei Yang, Zi Zhen Feng, Wei Chen, Ching Yuan Wu, Ying Jan Wang, Lu Ping Chow, Xiao Feng Zhu, Yi Xin Zeng, Hui Kuan Lin

Academic Institute

Research output: Contribution to journal › Article › peer-review

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Abstract

Understanding the mechanism by which cell growth, migration, polyploidy, and tumorigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression on Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy.

Original language	English (US)
Article number	6641
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7641
State	Published - Mar 2015

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Xu, D., Li, C. F., Zhang, X., Gong, Z., Chan, C. H., Lee, S. W., Jin, G., Rezaeian, A. H., Han, F., Wang, J., Yang, W. L., Feng, Z. Z., Chen, W., Wu, C. Y., Wang, Y. J., Chow, L. P., Zhu, X. F., Zeng, Y. X., & Lin, H. K. (2015). Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis. Nature Communications, 6, Article 6641. https://doi.org/10.1038/ncomms7641

@article{bcca7101f0254267ad0fa2d8ee22b29d,

title = "Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis",

abstract = "Understanding the mechanism by which cell growth, migration, polyploidy, and tumorigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression on Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy.",

author = "Dazhi Xu and Li, {Chien Feng} and Xian Zhang and Zhaohui Gong and Chan, {Chia Hsin} and Lee, {Szu Wei} and Guoxiang Jin and Rezaeian, {Abdol Hossein} and Fei Han and Jing Wang and Yang, {Wei Lei} and Feng, {Zi Zhen} and Wei Chen and Wu, {Ching Yuan} and Wang, {Ying Jan} and Chow, {Lu Ping} and Zhu, {Xiao Feng} and Zeng, {Yi Xin} and Lin, {Hui Kuan}",

note = "Funding Information: We thank Dr K.I. Nakayama for Skp2−/− mice and Drs M.C. Hung, E. Bernstein, W. Wei and J.Y. Ji for cells and reagents. We also thank Dr W. Zhang and his core facility at the MD Anderson Cancer Center for performing the microarray analysis. Special thanks to S. Zhang for his technical support. We also thank Dr Z. Han for his assistance in flow cytometry analysis and confocal microscopy. This study was supported by CPRIT grant, NIH RO1 grants, R. Lee Clark Award, the MD Anderson Prostate SPORE Development Award (P50CA40388) and the MD Anderson prostate moonshot program to H.-K.L.; the National Natural Sciences Foundation of China (81372569) to D.X.; and the grant from the Department of Health in Taiwan (MOHW103-TD-B-111-05 and DOH102-TD-M-111-102001) to C.-F.L. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = mar,

doi = "10.1038/ncomms7641",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis

AU - Xu, Dazhi

AU - Li, Chien Feng

AU - Zhang, Xian

AU - Gong, Zhaohui

AU - Chan, Chia Hsin

AU - Lee, Szu Wei

AU - Jin, Guoxiang

AU - Rezaeian, Abdol Hossein

AU - Han, Fei

AU - Wang, Jing

AU - Yang, Wei Lei

AU - Feng, Zi Zhen

AU - Chen, Wei

AU - Wu, Ching Yuan

AU - Wang, Ying Jan

AU - Chow, Lu Ping

AU - Zhu, Xiao Feng

AU - Zeng, Yi Xin

AU - Lin, Hui Kuan

N1 - Funding Information: We thank Dr K.I. Nakayama for Skp2−/− mice and Drs M.C. Hung, E. Bernstein, W. Wei and J.Y. Ji for cells and reagents. We also thank Dr W. Zhang and his core facility at the MD Anderson Cancer Center for performing the microarray analysis. Special thanks to S. Zhang for his technical support. We also thank Dr Z. Han for his assistance in flow cytometry analysis and confocal microscopy. This study was supported by CPRIT grant, NIH RO1 grants, R. Lee Clark Award, the MD Anderson Prostate SPORE Development Award (P50CA40388) and the MD Anderson prostate moonshot program to H.-K.L.; the National Natural Sciences Foundation of China (81372569) to D.X.; and the grant from the Department of Health in Taiwan (MOHW103-TD-B-111-05 and DOH102-TD-M-111-102001) to C.-F.L. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/3

Y1 - 2015/3

N2 - Understanding the mechanism by which cell growth, migration, polyploidy, and tumorigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression on Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy.

AB - Understanding the mechanism by which cell growth, migration, polyploidy, and tumorigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression on Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy.

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M3 - Article

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VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6641

ER -

Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis

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