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BPTF regulates growth of adult and pediatric high-grade glioma through the MYC pathway

Oncogene volume 39, pages 2305–2327 (2020)Cite this article

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A Correction to this article was published on 22 January 2020

Abstract

High-grade gliomas (HGG) afflict both children and adults and respond poorly to current therapies. Epigenetic regulators have a role in gliomagenesis, but a broad, functional investigation of the impact and role of specific epigenetic targets has not been undertaken. Using a two-step, in vitro/in vivo epigenomic shRNA inhibition screen, we determine the chromatin remodeler BPTF to be a key regulator of adult HGG growth. We then demonstrate that BPTF knockdown decreases HGG growth in multiple pediatric HGG models as well. BPTF appears to regulate tumor growth through cell self-renewal maintenance, and BPTF knockdown leads these glial tumors toward more neuronal characteristics. BPTF’s impact on growth is mediated through positive effects on expression of MYC and MYC pathway targets. HDAC inhibitors synergize with BPTF knockdown against HGG growth. BPTF inhibition is a promising strategy to combat HGG through epigenetic regulation of the MYC oncogenic pathway.

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Fig. 1: Justification for BPTF investigation in GBM.
Fig. 2: Validation of independent BPTF growth effect in BT 145.
Fig. 3: BPTF growth effect in other cell lines.
Fig. 4: Effect of BPTF knockdown on differentiation and cell self-renewal.
Fig. 5: BPTF knockdown interaction with MYC and downstream effectors.
Fig. 6: Potential epigenetic-targeting compounds synergistic with BPTF knockdown.

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Acknowledgements

We would like to thank Dr William Pomerantz for his expertize and discussion of BPTF small molecule inhibitors, and Drs Stuart Orkin, Mark Kieran, and Jay Bradner for their advice at early stages of the project. We also acknowledge the University of Colorado Denver Research Histology Shared Resource, supported by the Cancer Center Support Grant (P30CA046934), as well as the University of Colorado Anschutz Medical Campus Advanced Light Microscopy Core Facility and Functional Genomics Core Facility, for their assistance. The Colorado Animal Imaging Shared Resource is supported by the NCI and the University of Colorado Cancer Center (P30CA046934).

Funding

This work was supported by the Luke’s Army Pediatric Cancer Research Fund St. Baldrick’s Scholar Award, a Hyundai Hope on Wheels Young Investigator award, a Morgan Adams Foundation grant, a Pedals for Pediatrics grant, and NICHD K12HD068372 (ALG).

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  1. These authors contributed equally: Andrew L. Kung, Rajeev Vibhakar

Authors and Affiliations

  1. Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Anschutz Medical Campus, RC1-N, Mail Stop 8302 12800 E. 19th Ave., Aurora, CO, 80045, USA

    Adam L. Green, John DeSisto, Patrick Flannery, Rakeb Lemma, Aaron Knox, Bridget Sanford, Rebecca O’Rourke, Erin Moroze, Ilango Balakrishnan, Etienne Danis, Zachary Nuss, Jean M. Mulcahy Levy, Sujatha Venkataraman, Nicholas Foreman, Ken Jones & Rajeev Vibhakar

  2. Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, CO, USA

    Adam L. Green, Jean M. Mulcahy Levy, Nicholas Foreman & Rajeev Vibhakar

  3. Bioinfo, Ottawa, ON, Canada

    Madeleine Lemieux

  4. Dana-Farber Cancer Institute, Boston, MA, USA

    Shakti Ramkissoon, Kristen Jones, Jennifer Perry, Allison F. O’Neill, Katherine Dunn, Benjamin Hubbell-Engler & Keith Ligon

  5. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Xu Hui

  6. Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University, Atlanta, GA, USA

    Deborah DeRyckere & Douglas K. Graham

  7. Department of Radiology, University of Colorado School of Medicine, Aurora, CO, USA

    Aaron Safadi & Natalie Serkova

  8. Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA

    Ahmed Gilani

  9. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Andrew L. Kung

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Correspondence to Adam L. Green.

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Green, A.L., DeSisto, J., Flannery, P. et al. BPTF regulates growth of adult and pediatric high-grade glioma through the MYC pathway. Oncogene 39, 2305–2327 (2020). https://doi.org/10.1038/s41388-019-1125-7

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