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

Cell Stem Cell. 2017 Aug 3;21(2):209-224.e7. doi: 10.1016/j.stem.2017.06.004. Epub 2017 Jul 14.

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.

Keywords: ASCL1; NOTCH; brain tumor; cancer stem cell; differentiation therapy; fate specification; glioblastoma; neuronal differentiation; pioneer transcription factor; self-renewal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology*
  • Cell Differentiation / genetics
  • Cell Lineage*
  • Chromatin / metabolism*
  • Disease Progression
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / genetics
  • Glioblastoma / pathology*
  • Humans
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Neurons / metabolism
  • Neurons / pathology*
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Sequence Analysis, RNA
  • Up-Regulation / genetics

Substances

  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin