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

Cell Rep
Authors
Keywords
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.

Year of Publication
2013
Journal
Cell Rep
Volume
3
Issue
5
Pages
1567-79
Date Published
2013 May 30
ISSN
2211-1247
URL
DOI
10.1016/j.celrep.2013.04.021
PubMed ID
23707066
PubMed Central ID
PMC3774301
Links
Grant list
U54 HG006991 / HG / NHGRI NIH HHS / United States
R01 NS032677 / NS / NINDS NIH HHS / United States
Howard Hughes Medical Institute / United States
U54 HG004570 / HG / NHGRI NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States
R01 CA160762 / CA / NCI NIH HHS / United States