3 years ago

ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells

ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells
Lilian Lee, Panagiotis Prinos, Xi Huang, Xiaoyang Lan, Hayden Selvadurai, Stephane Angers, Mathieu Lupien, Rochelle F. McAdam, Gary Bader, Madlen O’Connor, Fiona J. Coutinho, Peter B. Dirks, Cheryl H. Arrowsmith, Veronique Voisin, Ian D. Clarke, Mark Bernstein, Erick Ling, Kinjal Desai, Paul Guilhamon, Sunit Das, Nicole I. Park, Heather Whetstone, Gurnit Atwal, Michael D. Cusimano, Michelle Kushida, Ellen Langille, Robert J. Vanner

Summary

Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.

Publisher URL: http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(17)30230-8

DOI: 10.1016/j.stem.2017.06.004

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