Cell reports (Cambridge), 2013-05, Vol.3 (5), p.1567-1579
2013
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- Autor(en) / Beteiligte
- Titel
- An Aberrant Transcription Factor Network Essential for Wnt Signaling and Stem Cell Maintenance in Glioblastoma
- Ist Teil von
- Cell reports (Cambridge), 2013-05, Vol.3 (5), p.1567-1579
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2013
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. [Display omitted] •Epigenomic profiles of glioblastoma stem cells and comparators•An aberrant network of developmental transcription factors in cancer stem cells•ASCL1 is essential for glioblastoma stem cell maintenance and tumorigenicity•ASCL1 activates Wnt signaling by directly repressing the negative regulator DKK1 Glioblastoma brain tumors contain a highly tumorigenic subpopulation of cells with stem-like features. Using epigenomic profiling, Chi, Bernstein, and colleagues identify a set of developmental transcription factors normally repressed by Polycomb complexes that become activated in these stem-like cancer cells. One of these factors, ASCL1, is shown to be essential for glioblastoma stem cell maintenance and tumorigenicity and to function as an activator of Wnt signaling in this setting.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2211-1247eISSN: 2211-1247DOI: 10.1016/j.celrep.2013.04.021Titel-ID: cdi_doaj_primary_oai_doaj_org_article_61ad20f8b8db4ae4a36b359023e2d865
- Format
- –
- Schlagworte
- ASCL1 protein, Astrocytes - cytology, Astrocytes - metabolism, Basic Helix-Loop-Helix Transcription Factors - antagonists & inhibitors, Basic Helix-Loop-Helix Transcription Factors - genetics, Basic Helix-Loop-Helix Transcription Factors - metabolism, Chromatin - metabolism, Epigenomics, Gene Expression Regulation, Neoplastic, Glioblastoma - metabolism, Glioblastoma - pathology, Humans, Intercellular Signaling Peptides and Proteins - genetics, Intercellular Signaling Peptides and Proteins - metabolism, Lymphoid Enhancer-Binding Factor 1 - genetics, Lymphoid Enhancer-Binding Factor 1 - metabolism, Neoplastic Stem Cells - cytology, Neoplastic Stem Cells - metabolism, RNA Interference, RNA, Small Interfering - metabolism, Tumor Cells, Cultured, Wnt Proteins - metabolism, Wnt Signaling Pathway