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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    • "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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    ABSTRACT: Histone 3 lysine 4 trimethylation (H3K4me3) is known to be associated with transcriptionally active or poised genes and required for postnatal neurogenesis within the subventricular zone (SVZ) in the rodent model. Previous comparisons have shown significant correlation between baboon (Papio anubis) and human brain. In this study, we demonstrate that chromatin activation mark H3K4me3 is present in undifferentiated progenitor cells within the SVZ of adult baboon brain. To identify the targets and regulatory role of H3K4me3 within the baboon SVZ, we developed a technique to purify undifferentiated SVZ cells while preserving the endogenous nature without introducing culture artifact to maintain the in vivo chromatin state for genome-wide studies (ChIP-Seq and RNA-Seq). Overall, H3K4me3 is significantly enriched for genes involved in cell cycle, metabolism, protein synthesis, signaling pathways, and cancer mechanisms. Additionally, we found elevated levels of H3K4me3 in the MRI-classified SVZ-associated Glioblastoma Multiforme (GBM), which has a transcriptional profile that reflects the H3K4me3 modifications in the undifferentiated progenitor cells of the baboon SVZ. Our findings highlight the importance of H3K4me3 in coordinating distinct networks and pathways for life-long neurogenesis, and suggest that subtypes of GBM could occur, at least in part, due to aberrant H3K4me3 epigenetic regulation.
    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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    ABSTRACT: The existence of subpopulations of cells in cancers with increased tumor-initiating capacities and self-renewal potential, often termed "cancer stem cells," is a much discussed and key area of cancer biology. Such cellular heterogeneity is very important because of its impact on therapy and especially states of treatment resistance. A major question is whether there is plasticity for evolution of these cell states during tumorigenesis that can involve movement between cell populations in a reversible fashion. In this review, we discuss the possible role of epigenetic abnormalities as well as genetic alterations in such dynamics and in the creation of cellular heterogeneity in cancers of all types.
    Molecular cell 06/2014; 54(5):716-727. DOI:10.1016/j.molcel.2014.05.015 · 14.02 Impact Factor
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    ABSTRACT: ASCL1 is an important regulatory transcription factor in pulmonary neuroendocrine (NE) cell development, but its value as a biomarker of NE differentiation in lung adenocarcinoma (AD) and as a potential prognostic biomarker remains unclear. We examined ASCL1 expression in lung cancer samples of varied histologic subtype, clinical outcome and smoking status and compared with expression of traditional NE markers. ASCL1 mRNA expression was found almost exclusively in smokers with AD, in contrast to non-smokers and other lung cancer subtypes. ASCL1 protein expression by immunohistochemical (IHC) analysis correlated best with synaptophysin compared with chromogranin and CD56/NCAM. Analysis of a compendium of 367 microarray-based gene expression profiles in stage I lung adenocarcinomas identified significantly higher expression levels of the RET oncogene in ASCL1-positive tumors (ASCL1(+)) compared with ASCL1(-) tumors (q-value <10(-9)). High levels of RET expression in ASCL1(+) but not in ASCL1(-) tumors was associated with significantly shorter overall survival (OS) in stage 1 (P=0.007) and in all AD (P=0.037). RET protein expression by IHC had an association with OS in the context of ASCL1 expression. In silico gene set analysis and in vitro experiments by ASCL1 shRNA in AD cells with high endogenous expression of ASCL1 and RET implicated ASCL1 as a potential upstream regulator of the RET oncogene. Also, silencing ASCL1 in AD cells markedly reduced cell growth and motility. These results suggest that ASCL1 and RET expression defines a clinically relevant subgroup of ∼10% of AD characterized by NE differentiation.Oncogene advance online publication, 16 September 2013; doi:10.1038/onc.2013.359.
    Oncogene 09/2013; 74(19 Supplement). DOI:10.1038/onc.2013.359 · 8.46 Impact Factor
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