Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells |
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| Authors: | Lee Jeongwu Son Myung Jin Woolard Kevin Donin Nicholas M Li Aiguo Cheng Chui H Kotliarova Svetlana Kotliarov Yuri Walling Jennifer Ahn Susie Kim Misuk Totonchy Mariam Cusack Thomas Ene Chibawanye Ma Hilary Su Qin Zenklusen Jean Claude Zhang Wei Maric Dragan Fine Howard A |
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| Affiliation: | Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. |
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| 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. |
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