Krüppel-Like Family of Transcription Factor 9, a Differentiation-Associated Transcription Factor, Suppresses Notch1 Signaling and Inhibits Glioblastoma-Initiating Stem Cells§

Authors

  • Mingyao Ying,

    1. Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA
    2. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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  • Yingying Sang,

    1. Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA
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  • Yunqing Li,

    1. Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA
    2. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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  • Hugo Guerrero-Cazares,

    1. Department of Neurosurgery, and Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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  • Alfredo Quinones-Hinojosa,

    1. Department of Neurosurgery, and Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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  • Angelo L. Vescovi,

    1. Department of Biotechnology and Biosciences, University of Milan Bicocca, Milan, Italy
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  • Charles G. Eberhart,

    1. Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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  • Shuli Xia,

    1. Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA
    2. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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  • John Laterra

    Corresponding author
    1. Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA
    2. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
    3. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
    4. Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
    • Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, Maryland 21205, USA
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    • Telephone: 443-923-2679; Fax: 443-923-2695


  • Author contributions: M.Y.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; Y.S., Y.L., and S.X.: collection and assembly of data, final approval of manuscript; H.G.-C., A.Q.-H., A.L.V., and C.G.E.: providing material, final approval of manuscript; J.L.: conception and design, financial support, administrative support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • First published online in STEM CELLS EXPRESS November 18, 2010.

  • §

    Disclosure of potential conflicts of interest is found at the end of this article.

Abstract

Tumor-initiating stem cells (alternatively called cancer stem cells, CSCs) are a subpopulation of tumor cells that plays unique roles in tumor propagation, therapeutic resistance, and tumor recurrence. It is becoming increasingly important to understand the molecular signaling that regulates the self-renewal and differentiation of CSCs. Transcription factors are critical for the regulation of normal and neopolastic stem cells. Here, we examined the expression and function of the Krüppel-like family of transcription factors (KLFs) in human glioblastoma (GBM)-derived neurosphere lines and low-passage primary GBM-derived neurospheres that are enriched for tumor-initiating stem cells. We identify KLF9 as a relatively unique differentiation-induced transcription factor in GBM-derived neurospheres. KLF9 is shown to induce neurosphere cell differentiation, inhibit neurosphere formation, and inhibit neurosphere-derived xenograft growth in vivo. We also show that KLF9 regulates GBM neurosphere cells by binding to the Notch1 promoter and suppressing Notch1 expression and downstream signaling. Our results show for the first time that KLF9 has differentiating and tumor-suppressing functions in tumor-initiating stem cells. STEM CELLS 2011;29:20–31

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