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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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).
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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The authors declare that they have no conflict of interest.
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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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