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

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  • Dazhi Xu

    (State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center
    M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA)

  • Chien-Feng Li

    (National Institute of Cancer Research, National Health Research Institutes
    Chi-Mei Foundational Medical Center
    Southern Taiwan University
    Institute of Clinical Medicine, Kaohsiung Medical University)

  • 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
    Institute of Biochemistry and Molecular Biology, Ningbo University School of Medicine)

  • Chia-Hsin Chan

    (M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
    Present address: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11790, 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
    Chiayi Chang Gung Memorial Hospital
    School of Traditional Chinese Medicine, College of Medicine, Chang Gung University)

  • 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
    The University of Texas Graduate School of Biomedical Sciences at Houston
    Graduate Institute of Basic Medical Science, China Medical University
    Asia University)

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.

Suggested Citation

  • 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 , 2015. "Skp2–MacroH2A1–CDK8 axis orchestrates G2/M transition and tumorigenesis," Nature Communications, Nature, vol. 6(1), pages 1-14, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7641
    DOI: 10.1038/ncomms7641
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