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

Bioinformatics Program, Boston University, Boston, MA 02215, USA.
Cell Reports (Impact Factor: 8.36). 05/2013; 3(5). DOI: 10.1016/j.celrep.2013.04.021
Source: PubMed


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.

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Available from: Samuel D Rabkin, Oct 27, 2015
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    • "While MLL/H3K4me3 functions in adult neurogenesis, the suspicion of SVZ as the origin for subtypes of brain tumors3840 raises the concern that, similar to hematologic cancer1920, deregulation of this epigenetic mark could cause cancer associated with this germinal niche. We found elevated levels of H3K4me3 in MRI-classified group I and II GBM specimens, reminiscent of a recent study of chromatin status mapping, in that enriched occupancy of H3K4me3 was found in established GBM cell lines44. Although previous studies have identified mutations and the resulting abnormal expression (eg. "
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    Scientific Reports 06/2014; 4:5371. DOI:10.1038/srep05371 · 5.58 Impact Factor
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    • "For example, in AML, the AML-CSCs and non-CSCs differ in their histone modification patterns (H3K4me3 and H3K27me3) but not DNA methylation patterns (Yamazaki et al., 2013). In GBMs, the GBM-CSCs have aberrant activation of multiple transcription factors because of a loss of the polycomb mark H3K27me3 from their promoters (Rheinbay et al., 2013). "
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