Article

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

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.

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Available from: Samuel D Rabkin, Oct 27, 2015
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    • "ASCL1 alone or together with other factors converts non-neural somatic cells into neurons (Amamoto and Arlotta, 2014). ASCL1 has also been implicated in cancerous phenotypes of several types carcinomas (Huang et al., 2014; Jiang et al., 2009; Rheinbay et al., 2013; Wylie et al., 2015). In this study, we provide evidence that ascl1 is a maternal gene enriched in the animal pole. "
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    • "As early as 2 weeks after retroviral infection, and consistent with effective Notch inhibition in PDGF + Trp53 À/À Rbpj À/À gliomas, Cre + Hes5::GFP + tumor cells were reduced by >2/3 and cells expressing the Notch-repressed target Mash1 increased 6-fold compared to PDGF + Trp53 À/À tumors (Figures 2B and 2C). The few residual Hes5::GFP cells in PDGF + Trp53 À/À Rbpj À/À gliomas expressed Mash1 and Olig2, two transcription factors involved in glioma development and proliferation (Figures 2C, S2A, and S2B; data not shown) (Mehta et al., 2011; Rheinbay et al., 2013). Sox2 expression was not affected by Rbpj-deletion, indicating that the cells retained stem/ progenitor identity (Figure S2C). "
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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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