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 and Hui-Kuan Lin ()
Additional contact information
Dazhi Xu: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center
Chien-Feng Li: National Institute of Cancer Research, National Health Research Institutes
Xian Zhang: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Zhaohui Gong: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Chia-Hsin Chan: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Szu-Wei Lee: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Guoxiang Jin: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Abdol-Hossein Rezaeian: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Fei Han: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Jing Wang: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Wei-Lei Yang: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Zi-Zhen Feng: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Wei Chen: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Ching-Yuan Wu: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Ying-Jan Wang: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Lu-Ping Chow: Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University
Xiao-Feng Zhu: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center
Yi-Xin Zeng: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center
Hui-Kuan Lin: M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7641

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