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

• Published in: Cell stem cell Vol. 21; no. 2; pp. 209 - 224.e7
• Main Authors: Park, Nicole I., Guilhamon, Paul, Desai, Kinjal, McAdam, Rochelle F., Langille, Ellen, O’Connor, Madlen, Lan, Xiaoyang, Whetstone, Heather, Coutinho, Fiona J., Vanner, Robert J., Ling, Erick, Prinos, Panagiotis, Lee, Lilian, Selvadurai, Hayden, Atwal, Gurnit, Kushida, Michelle, Clarke, Ian D., Voisin, Veronique, Cusimano, Michael D., Bernstein, Mark, Das, Sunit, Bader, Gary, Arrowsmith, Cheryl H., Angers, Stephane, Huang, Xi, Lupien, Mathieu, Dirks, Peter B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.08.2017
• Subjects: ASCL1; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Brain Neoplasms - genetics; Brain Neoplasms - pathology; brain tumor; cancer stem cell; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Differentiation - genetics; Cell Lineage; Chromatin - metabolism; differentiation therapy; Disease Progression; Enhancer Elements, Genetic - genetics; fate specification; Gene Expression Regulation, Neoplastic; glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; neuronal differentiation; Neurons - metabolism; Neurons - pathology; NOTCH; pioneer transcription factor; Promoter Regions, Genetic - genetics; Protein Binding; self-renewal; Sequence Analysis, RNA; Up-Regulation - genetics; glioblastoma; cancer stem cell; fate specification; pioneer transcription factor; NOTCH; brain tumor; ASCL1; differentiation therapy; self-renewal; neuronal differentiation
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2017.06.004

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. [Display omitted] •GSCs can be classified into two subgroups based on ASCL1 expression•ASCL1 is required for GSCs to undergo neuronal lineage differentiation•ASCL1hi GSCs are responsive to Notch pathway inhibitors•ASCL1 binds closed chromatin to activate target genes that drive neuronal fate Glioblastoma is characterized by a block in cellular differentiation. Park et al. identify a subset of glioblastoma stem cells (GSCs) that express high levels of the proneural transcription factor ASCL1 and differentiate in response to Notch inhibition, effectively abrogating their stemness properties and tumorigenic potential.