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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Rheinbay, E; Suvà, ML; Gillespie, SM; Wakimoto, H; Patel, AP; Shahid, M; Oksuz, O; Rabkin, SD; Martuza, RL; Rivera, MN; Louis, DN; Kasif, S; Chi, AS; Bernstein, BE

Published Date

  • May 30, 2013

Published In

Volume / Issue

  • 3 / 5

Start / End Page

  • 1567 - 1579

PubMed ID

  • 23707066

Pubmed Central ID

  • PMC3774301

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2013.04.021


  • eng

Conference Location

  • United States