Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells.

Abstract

Despite similarities between tumor-initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues and by converting otherwise cytostatic signals to proproliferative signals.

• Authors: Jeongwu Lee, Myung Jin Son, Kevin Woolard, Nicholas M Donin, Aiguo Li, Chui H Cheng, Svetlana Kotliarova, Yuri Kotliarov, Jennifer Walling, Susie Ahn, Misuk Kim, Mariam Totonchy, Thomas Cusack, Chibawanye Ene, Hilary Ma, Qin Su, Jean Claude Zenklusen, Wei Zhang, Dragan Maric, Howard A Fine
• Journal: Cancer cell (Cancer Cell) Vol. 13 Issue 1 Pg. 69-80 (Jan 2008) ISSN: 1535-6108 [Print] United States
• PMID: 18167341 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Bone Morphogenetic Proteins
• Ciliary Neurotrophic Factor
• Cytokines
• DNA-Binding Proteins
• STAT3 Transcription Factor
• Transcription Factors
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2
• Bone Morphogenetic Protein Receptors, Type I

Topics

• Animals
• Astrocytes (pathology)
• Bone Morphogenetic Protein Receptors, Type I (metabolism)
• Bone Morphogenetic Proteins (metabolism, pharmacology)
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Ciliary Neurotrophic Factor (metabolism, pharmacology)
• Cytokines (pharmacology)
• DNA Methylation (drug effects)
• DNA-Binding Proteins (metabolism)
• Enhancer of Zeste Homolog 2 Protein
• Epigenesis, Genetic (drug effects)
• Gene Silencing (drug effects)
• Glioblastoma (genetics, pathology)
• Humans
• Mice
• Mice, SCID
• Neoplastic Stem Cells (pathology)
• Phosphorylation (drug effects)
• Polycomb Repressive Complex 2
• Promoter Regions, Genetic (genetics)
• STAT3 Transcription Factor (metabolism)
• Transcription Factors (metabolism)