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Epigenetic modulation of a miR-296-5p:HMGA1 axis regulates Sox2 expression and glioblastoma stem cells

Oncogene volume 35, pages 4903–4913 (2016)Cite this article

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Abstract

Solid malignancies contain subsets of multipotent cells that grow as spheres and efficiently propagate tumors in xenograft models, reflecting a stem-like, self-renewing and tumor-propagating phenotype. These cancer ‘stem cells (SCs)’ have been shown to maintain tumor growth, contribute to resistance and drive tumor recurrence. Cancer cell stemness is dynamically influenced by epigenetic mechanisms and differentially regulated coding and noncoding RNAs. How these mechanisms specifically contribute to the generation and/or maintenance of cancer SCs remains unclear. This study identifies a novel epigenetically regulated circuit that integrates microRNA, chromatin remodeling and the reprogramming transcription factor Sox2 to regulate glioblastoma (GBM)-propagating SCs. We show that miR-296-5p expression is repressed in a DNA methylation-dependent manner under conditions that promote GBM cell stemness and that miR-296-5p inhibits GBM cell stemness and their capacity to self-renew as spheres and propagate glioma xenografts in vivo. We show that the chromatin remodeling protein HMGA1 functions as a downstream effector of these biological responses to miR-296-5p and regulates Sox2 expression, a master driver of cell stemness, by modifying chromatin architecture at the Sox2 promoter. These results show for the first time that miR-296-5p inhibits transcriptional mechanisms that support GBM SCs and identify a miR-296-5p:HMGA1:Sox2 axis as a novel regulator of GBM SCs and candidate pathway for targeting therapies directed at depleting tumors of their tumor-propagating stem cell subsets.

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Acknowledgements

This work was supported by grants from the American Brain Tumor Association (to HL-B), and the United States NIH Grants R01NS073611 (to JL) and R01NS070024 (to AQ-H).

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Authors and Affiliations

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

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

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

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

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

    H Guerrero-Cázares & A Quiñones-Hinojosa

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

    A Quiñones-Hinojosa & J Laterra

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

    A Quiñones-Hinojosa & J Laterra

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Correspondence to J Laterra.

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Competing interests

Dr Laterra’s and Dr Quinones-Hinojosa’s work has been funded by the NIH.

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Lopez-Bertoni, H., Lal, B., Michelson, N. et al. Epigenetic modulation of a miR-296-5p:HMGA1 axis regulates Sox2 expression and glioblastoma stem cells. Oncogene 35, 4903–4913 (2016). https://doi.org/10.1038/onc.2016.22

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