The Zinc Finger Transcription Factor ZFX Is Required for Maintaining the Tumorigenic Potential of Glioblastoma Stem Cells

Authors

  • Xiaoguang Fang,

    1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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  • Zhi Huang,

    1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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  • Wenchao Zhou,

    1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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  • Qiulian Wu,

    1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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  • Andrew E. Sloan,

    1. Department of Neurological Surgery, University Hospitals-Case Medical Center & Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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  • Gaoliang Ouyang,

    1. The State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, People's Republic of China
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  • Roger E. McLendon,

    1. Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
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  • Jennifer S. Yu,

    1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    2. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
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  • Jeremy N. Rich,

    1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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  • Shideng Bao

    Corresponding author
    1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    • Correspondence: Shideng Bao, Ph.D., Department of Stem Cell Biology & Regenerative Medicine, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, NE30, Cleveland, Ohio 44195, USA. Telephone: +1-216-636-1009; fax: +1-216-636-5454; e-mail: baos@ccf.org

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Abstract

Glioblastomas are highly lethal brain tumors containing tumor-propagating glioma stem cells (GSCs). The molecular mechanisms underlying the maintenance of the GSC phenotype are not fully defined. Here we demonstrate that the zinc finger and X-linked transcription factor (ZFX) maintains GSC self-renewal and tumorigenic potential by upregulating c-Myc expression. ZFX is differentially expressed in GSCs relative to non-stem glioma cells and neural progenitor cells. Disrupting ZFX by shRNA reduced c-Myc expression and potently inhibited GSC self-renewal and tumor growth. Ectopic expression of c-Myc to its endogenous level rescued the effects caused by ZFX disruption, supporting that ZFX controls GSC properties through c-Myc. Furthermore, ZFX binds to a specific sequence (GGGCCCCG) on the human c-Myc promoter to upregulate c-Myc expression. These data demonstrate that ZFX functions as a critical upstream regulator of c-Myc and plays essential roles in the maintenance of the GSC phenotype. This study also supports that c-Myc is a dominant driver linking self-renewal to malignancy. Stem Cells 2014;32:2033–2047

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