Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke

Authors

  • Yung-Luen Yu,

    Corresponding author
    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
    2. Department of Biotechnology, Asia University, Taichung, Taiwan
    • Yung-Luen Yu, Tel: +886 4 22052121 ext. 7933; Fax: +886 4 22333496

      Mien-Chie Hung, Tel: +1 713 792 3668; Fax: +1 713 794 3270

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    • These authors contributed equally to this work.

  • Ruey-Hwang Chou,

    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
    2. Department of Biotechnology, Asia University, Taichung, Taiwan
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    • These authors contributed equally to this work.

  • Woei-Cherng Shyu,

    1. Graduate Institute of Immunology, Translational Medicine Research Center, Center for Neuropsychiatry, China Medical University, Taichung, Taiwan
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    • These authors contributed equally to this work.

  • Shu-Ching Hsieh,

    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
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  • Chen-Shiou Wu,

    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
    2. The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan
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  • Shu-Ya Chiang,

    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
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  • Wei-Jung Chang,

    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
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  • Jia-Ni Chen,

    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
    2. The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan
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  • Yen-Ju Tseng,

    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
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  • Yu-Hsuan Lin,

    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
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  • Wei Lee,

    1. Graduate Institute of Immunology, Translational Medicine Research Center, Center for Neuropsychiatry, China Medical University, Taichung, Taiwan
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  • Su-Peng Yeh,

    1. Division of Hematology and Oncology, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
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  • Jennifer L. Hsu,

    1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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  • Cheng-Chieh Yang,

    1. Department of Stomatology, Taipei Veteran General Hospital, and Dental School, National Yang-Ming University, Taipei, Taiwan
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  • Shih-Chieh Hung,

    1. Stem Cell Laboratory, Department of Medical Research and Education, Orthopaedics and Traumatology, Taipei Veterans General Hospital, Institute of Clinical Medicine, Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
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  • Mien-Chie Hung

    Corresponding author
    1. Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
    2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
    • Yung-Luen Yu, Tel: +886 4 22052121 ext. 7933; Fax: +886 4 22333496

      Mien-Chie Hung, Tel: +1 713 792 3668; Fax: +1 713 794 3270

    Search for more papers by this author

Abstract

EZH2 plays an important role in stem cell renewal and maintenance by inducing gene silencing via its histone methyltransferase activity. Previously, we showed that EZH2 downregulation enhances neuron differentiation of human mesenchymal stem cells (hMSCs); however, the underlying mechanisms of EZH2-regulated neuron differentiation are still unclear. Here, we identify Smurf2 as the E3 ubiquitin ligase responsible for the polyubiquitination and proteasome-mediated degradation of EZH2, which is required for neuron differentiation. A ChIP-on-chip screen combined with gene microarray analysis revealed that PPARγ was the only gene involved in neuron differentiation with significant changes in both its modification and expression status during differentiation. Moreover, knocking down PPARγ prevented cells from undergoing efficient neuron differentiation. In animal model, rats implanted with intracerebral EZH2-knocked-down hMSCs or hMSCs plus treatment with PPARγ agonist (rosiglitazone) showed better improvement than those without EZH2 knockdown or rosiglitazone treatment after a stroke. Together, our results support Smurf2 as a regulator of EZH2 turnover to facilitate PPARγ expression, which is specifically required for neuron differentiation, providing a molecular mechanism for clinical applications in the neurodegenerative diseases.

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