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DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2

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Abstract

Cancer stem-like cells represent poorly differentiated multipotent tumor-propagating cells that contribute disproportionately to therapeutic resistance and tumor recurrence. Transcriptional mechanisms that control the phenotypic conversion of tumor cells lacking tumor-propagating potential to tumor-propagating stem-like cells remain obscure. Here we show that the reprogramming transcription factors Oct4 and Sox2 induce glioblastoma cells to become stem-like and tumor–propagating via a mechanism involving direct DNA methyl transferase (DNMT) promoter transactivation, resulting in global DNA methylation- and DNMT-dependent downregulation of multiple microRNAs (miRNAs). We show that one such downregulated miRNA, miRNA-148a, inhibits glioblastoma cell stem-like properties and tumor-propagating potential. This study identifies a novel and targetable molecular circuit by which glioma cell stemness and tumor-propagating capacity are regulated.

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Acknowledgements

We thank Daniel Trageser for technical assistance. This work was financially supported by grants from the American Brain Tumor Association (YL), James S McDonnell Foundation (JL), and the United States NIH grants RO1NS073611 (JL) and R01NS070024 (AQ-H).

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Author notes

  1. J Laterra and Y Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA

    H Lopez-Bertoni, B Lal, A Li, M Caplan, J Laterra & Y Li

  2. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA,

    H Lopez-Bertoni, B Lal, J Laterra & Y Li

  3. Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA,

    H Guerrero-Cázares & A Quiñones-Hinojosa

  4. Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA,

    C G Eberhart

  5. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA,

    A Quiñones-Hinojosa & J Laterra

  6. Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA,

    A Quiñones-Hinojosa & J Laterra

  7. Institute of Reconstructive Neurobiology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany,

    M Glas & B Scheffler

  8. Department of Neurology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany,

    M Glas

  9. Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany,

    M Glas

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  1. H Lopez-Bertoni
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  2. B Lal
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  3. A Li
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  10. J Laterra
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  11. Y Li
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Correspondence to J Laterra or Y Li.

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Lopez-Bertoni, H., Lal, B., Li, A. et al. DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2. Oncogene 34, 3994–4004 (2015). https://doi.org/10.1038/onc.2014.334

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  • DOI: https://doi.org/10.1038/onc.2014.334

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