An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma

Cell Rep. 2013 May 30;3(5):1567-79. doi: 10.1016/j.celrep.2013.04.021. Epub 2013 May 23.

Abstract

Glioblastoma (GBM) is thought to be driven by a subpopulation of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity yet remain poorly understood. Here, we present a comparative analysis of chromatin state in GBM CSCs that reveals widespread activation of genes normally held in check by Polycomb repressors. These activated targets include a large set of developmental transcription factors (TFs) whose coordinated activation is unique to the CSCs. We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. We show that ASCL1 is essential for the maintenance and in vivo tumorigenicity of GBM CSCs. Genome-wide binding profiles for ASCL1 and the Wnt effector LEF-1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections among ASCL1, Wnt signaling, and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Chromatin / metabolism
  • Epigenomics
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Tumor Cells, Cultured
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway

Substances

  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • RNA, Small Interfering
  • Wnt Proteins

Associated data

  • GEO/GSE46016