Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Pathway Inhibits Differentiation of Glioblastoma-Initiating Cells

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)69-80
Number of pages12
JournalCancer Cell
Volume13
Issue number1
DOIs
StatePublished - Jan 8 2008

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Keywords

  • CELLCYCLE
  • MOLNEURO

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Lee, J., Son, M. J., Woolard, K., Donin, N. M., Li, A., Cheng, C. H., Kotliarova, S., Kotliarov, Y., Walling, J., Ahn, S., Kim, M., Totonchy, M., Cusack, T., Ene, C., Ma, H., Su, Q., Zenklusen, J. C., Zhang, W., Maric, D., & Fine, H. A. (2008). Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Pathway Inhibits Differentiation of Glioblastoma-Initiating Cells. Cancer Cell, 13(1), 69-80. https://doi.org/10.1016/j.ccr.2007.12.005