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YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells

Oncogene volume 35, pages 4256–4268 (2016)Cite this article

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Abstract

Postnatal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells of origin for the SHH-associated subgroup of medulloblastoma, is driven by Sonic hedgehog (Shh) and insulin-like growth factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is upregulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh subgroup of medulloblastoma in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and MBCs and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.

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Acknowledgements

We are grateful for the resources available from the Winship Cancer Institute (WCI)- Pathology Core Lab for paraffin embedding of tissues. We acknowledge the assistance provided by Neil Anthony (Integrated Imaging Core, Emory University) during image acquisition and analysis. We thank Tobey Macdonald, Matthew Schniederjan and Megan Hamling from Children’s Healthcare of Atlanta (CHOA) for providing human medulloblastoma tissue sections. We also thank Daniel Brat and Carol Tucker-Burden for assistance in slice culture experiments. We greatly appreciate the suggestions and feedback from Nada Jabado, Dan Brat, Sandra Dunn, Tracy Ann-Read, Renee Read and Tamara Caspary. This work has been supported by grants to AMK from the NIH (NINDS R01 NS061070), CURE Childhood Cancer Foundation and Winship Cancer Institute (P30 center grant—CA138292). AD acknowledges Alex Lemonade Stand Foundation and Northwestern Mutual Foundation for Young Investigator Award and Imaging studies were supported by a pilot grant to AD from the Integrated Cellular Imaging (ICI) core at Emory University.

Author contributions

AD and AMK designed the research. AD, MRo, MRe, CM and AM performed the experiments and analyzed the data. AG and JLW provided YAP(LoxP) mice and assisted with their husbandry. MRo, MRe, JLW, MDT and SA edited the manuscript before submission. AD and AMK wrote the paper. All the authors read and commented on the manuscript and approved the final version.

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  1. M Robitaille and M Remke: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Oncology, Emory University, Atlanta, GA, USA

    A Dey, C Maier, A Malhotra & A M Kenney

  2. Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

    M Robitaille & S Angers

  3. Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    M Robitaille & S Angers

  4. The Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick Children, Toronto, Ontario, Canada

    M Remke & M D Taylor

  5. Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    A Gregorieff & J L Wrana

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  1. A Dey
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Dey, A., Robitaille, M., Remke, M. et al. YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells. Oncogene 35, 4256–4268 (2016). https://doi.org/10.1038/onc.2015.491

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