An Aberrant Transcription Factor Network Essential for Wnt Signaling and Stem Cell Maintenance in Glioblastoma

作者：Rheinbay Esther; Suva Mario L; Gillespie Shawn M; Wakimoto Hiroaki; Patel Anoop P; Shahid Mohammad; Oksuz Ozgur; Rabkin Samuel D; Martuza Robert L; Rivera Miguel N; Louis David N; Kasif Simon; Chi Andrew S^*; Bernstein Bradley E

来源：Cell Reports, 2013, 3(5): 1567-1579.

DOI：10.1016/j.celrep.2013.04.021

Glioblastoma (GBM) is thought to be driven by a sub-population 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.

• 出版日期2013-5