1. BPTF regulates growth of adult and pediatric high-grade glioma through the MYC pathway
- Author
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Ilango Balakrishnan, Douglas K. Graham, Nicholas K. Foreman, Bridget Sanford, Benjamin Hubbell-Engler, Adam L. Green, Kristen L Jones, Sujatha Venkataraman, Patrick Flannery, Jennifer A. Perry, John DeSisto, Xu Hui, Ahmed Gilani, Aaron J. Knox, Shakti Ramkissoon, Andrew L. Kung, Madeleine E. Lemieux, Allison F. O'Neill, Deborah DeRyckere, Erin Moroze, Natalie J. Serkova, Kenneth L. Jones, Keith L. Ligon, Rajeev Vibhakar, Zachary Nuss, Aaron Safadi, Rebecca O’Rourke, Rakeb Lemma, Katherine Dunn, Jean M. Mulcahy Levy, and Etienne Danis
- Subjects
0301 basic medicine ,Cancer Research ,High-Grade Glioma ,Cell ,Regulator ,MYC ,Biology ,Article ,Small hairpin RNA ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Epigenetics ,Molecular Biology ,Epigenomics ,Gene knockdown ,In vitro ,Chromatin ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,DIPG ,Cancer research ,BPTF - 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.
- Published
- 2019