• Open Access

MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells§

Authors

  • Kaushal Joshi,

    1. Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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  • Yeshavanth Banasavadi-Siddegowda,

    1. Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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  • Xiaokui Mo,

    1. Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA
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  • Sung-Hak Kim,

    1. Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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  • Ping Mao,

    1. Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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  • Cenk Kig,

    1. Laboratory of Biosignaling & Therapeutics, Department of Cellular and Molecular Medicine, KULeuven, Leuven, Belgium
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  • Diana Nardini,

    1. Cancer and Blood Diseases Institute at Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
    2. Division of Experimental Hematology and Cancer Biology at Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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  • Robert W. Sobol,

    1. Department of Pharmacology & Chemical Biology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
    2. Department of Human Genetics, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
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  • Lionel M.L. Chow,

    1. Cancer and Blood Diseases Institute at Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
    2. Division of Experimental Hematology and Cancer Biology at Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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  • Harley I. Kornblum,

    1. Department of Psychiatry, University of California Los Angeles, Los Angeles, California, USA
    2. Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, USA
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  • Ronald Waclaw,

    1. Cancer and Blood Diseases Institute at Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
    2. Division of Experimental Hematology and Cancer Biology at Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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  • Monique Beullens,

    1. Laboratory of Biosignaling & Therapeutics, Department of Cellular and Molecular Medicine, KULeuven, Leuven, Belgium
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  • Ichiro Nakano

    Corresponding author
    1. Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
    • 385 Wiseman Hall, 410 W 12th St., Columbus, Ohio 43210, USA
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    • Telephone: 614-292-0358; Fax: 614-688-4882


  • Author contributions: K.J.: collection and/or assembly of data, administrative support, data analysis and interpretation, and manuscript writing; Y.B., S.K., P.M., C.K., D.N., and R.W.S.: collection and/or assembly of data; H.I.K.: provision of study material or patients, interpretation of data, and manuscript writing; L.M.L.C., R.W., and M.B.: collection and/or assembly of data and data analysis and interpretation; I.N.: conception and design, financial support, provision of study, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.

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

  • §

    first published online in STEM CELLS EXPRESS February 13, 2013.

Abstract

Glioblastoma multiforme (GBM) is a life-threatening brain tumor. Accumulating evidence suggests that eradication of glioma stem-like cells (GSCs) in GBM is essential to achieve cure. The transcription factor FOXM1 has recently gained attention as a master regulator of mitotic progression of cancer cells in various organs. Here, we demonstrate that FOXM1 forms a protein complex with the mitotic kinase MELK in GSCs, leading to phosphorylation and activation of FOXM1 in a MELK kinase-dependent manner. This MELK-dependent activation of FOXM1 results in a subsequent increase in mitotic regulatory genes in GSCs. MELK-driven FOXM1 activation is regulated by the binding and subsequent trans-phosphorylation of FOXM1 by another kinase PLK1. Using mouse neural progenitor cells (NPCs), we found that transgenic expression of FOXM1 enhances, while siRNA-mediated gene silencing diminishes neurosphere formation, suggesting that FOXM1 is required for NPC growth. During tumorigenesis, FOXM1 expression sequentially increases as cells progress from NPCs, to pretumorigenic progenitors and GSCs. The antibiotic Siomycin A disrupts MELK-mediated FOXM1 signaling with a greater sensitivity in GSC compared to neural stem cell. Treatment with the first-line chemotherapy agent for GBM, Temozolomide, paradoxically enriches for both FOXM1 (+) and MELK (+) cells in GBM cells, and addition of Siomycin A to Temozolomide treatment in mice harboring GSC-derived intracranial tumors enhances the effects of the latter. Collectively, our data indicate that FOXM1 signaling through its direct interaction with MELK regulates key mitotic genes in GSCs in a PLK1-dependent manner and thus, this protein complex is a potential therapeutic target for GBM. STEM Cells 2013;31:1051–1063

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