1. ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells
- Author
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Veronique Voisin, Gary D. Bader, Mark Bernstein, Xiaoyang Lan, Heather Whetstone, Xi Huang, Michelle Kushida, Madlen O’Connor, Mathieu Lupien, Ellen Langille, Erick Ling, Peter B. Dirks, Hayden J. Selvadurai, Sunit Das, Rochelle F. McAdam, Fiona J. Coutinho, Gurnit Atwal, Kinjal Desai, Cheryl H. Arrowsmith, Paul Guilhamon, Lilian Lee, Robert Vanner, Ian D. Clarke, Michael D. Cusimano, Stephane Angers, Panagiotis Prinos, and Nicole I. Park
- Subjects
0301 basic medicine ,endocrine system ,Carcinogenesis ,Cellular differentiation ,Notch signaling pathway ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Differentiation therapy ,Cancer stem cell ,Genetics ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Cell Lineage ,Promoter Regions, Genetic ,030304 developmental biology ,Neurons ,0303 health sciences ,Base Sequence ,Brain Neoplasms ,Sequence Analysis, RNA ,Pioneer factor ,Neurogenesis ,Cell Differentiation ,Cell Biology ,Chromatin ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,ASCL1 ,030104 developmental biology ,Enhancer Elements, Genetic ,Cancer research ,Disease Progression ,Neoplastic Stem Cells ,Molecular Medicine ,Stem cell ,Glioblastoma ,030217 neurology & neurosurgery ,Protein Binding - Abstract
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.
- Published
- 2017