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

doi:10.1016/j.ccr.2007.12.005

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 journal › Article › peer-review

367 Scopus citations

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 language	English (US)
Pages (from-to)	69-80
Number of pages	12
Journal	Cancer cell
Volume	13
Issue number	1
DOIs	https://doi.org/10.1016/j.ccr.2007.12.005
State	Published - Jan 8 2008
Externally published	Yes

Keywords

CELLCYCLE
MOLNEURO

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccr.2007.12.005

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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

Lee, J, Son, MJ, Woolard, K, Donin, NM, Li, A, Cheng, CH, Kotliarova, S, Kotliarov, Y, Walling, J, Ahn, S, Kim, M, Totonchy, M, Cusack, T, Ene, C , Ma, H, Su, Q, Zenklusen, JC, Zhang, W, Maric, D & Fine, HA 2008, 'Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Pathway Inhibits Differentiation of Glioblastoma-Initiating Cells', Cancer cell, vol. 13, no. 1, pp. 69-80. https://doi.org/10.1016/j.ccr.2007.12.005

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title = "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.",

keywords = "CELLCYCLE, MOLNEURO",

author = "Jeongwu Lee and Son, {Myung Jin} and Kevin Woolard and Donin, {Nicholas M.} and Aiguo Li and Cheng, {Chui H.} and Svetlana Kotliarova and Yuri Kotliarov and Jennifer Walling and Susie Ahn and Misuk Kim and Mariam Totonchy and Thomas Cusack and Chibawanye Ene and Hilary Ma and Qin Su and Zenklusen, {Jean Claude} and Wei Zhang and Dragan Maric and Fine, {Howard A.}",

note = "Funding Information: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We are grateful to Dr. Eugene Major for providing human fetal neural progenitor cells, and Dr. David Panchision and Dr. James Darnell for providing BMPR1B and STAT3C plasmids. We also thank NINDS sequencing facility and NINDS light image facility for their valuable contributions to this work. ",

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doi = "10.1016/j.ccr.2007.12.005",

language = "English (US)",

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AU - Lee, Jeongwu

AU - Son, Myung Jin

AU - Woolard, Kevin

AU - Donin, Nicholas M.

AU - Li, Aiguo

AU - Cheng, Chui H.

AU - Kotliarova, Svetlana

AU - Kotliarov, Yuri

AU - Walling, Jennifer

AU - Ahn, Susie

AU - Kim, Misuk

AU - Totonchy, Mariam

AU - Cusack, Thomas

AU - Ene, Chibawanye

AU - Ma, Hilary

AU - Su, Qin

AU - Zenklusen, Jean Claude

AU - Zhang, Wei

AU - Maric, Dragan

AU - Fine, Howard A.

N1 - Funding Information: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We are grateful to Dr. Eugene Major for providing human fetal neural progenitor cells, and Dr. David Panchision and Dr. James Darnell for providing BMPR1B and STAT3C plasmids. We also thank NINDS sequencing facility and NINDS light image facility for their valuable contributions to this work.

PY - 2008/1/8

Y1 - 2008/1/8

N2 - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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