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

Jeongwu Lee, Myung Jin Son, Kevin D 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

311 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Bone Morphogenetic Protein Receptors
Bone Morphogenetic Proteins
Glioblastoma
Epigenomics
Ciliary Neurotrophic Factor
Neural Stem Cells
Neoplastic Stem Cells
Cytostatic Agents
Transgenes
Cues

Keywords

  • CELLCYCLE
  • MOLNEURO

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Pathway Inhibits Differentiation of Glioblastoma-Initiating Cells. / Lee, Jeongwu; Son, Myung Jin; Woolard, Kevin D; 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.

In: Cancer Cell, Vol. 13, No. 1, 08.01.2008, p. 69-80.

Research output: Contribution to journalArticle

Lee, J, Son, MJ, Woolard, KD, 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
Lee, Jeongwu ; Son, Myung Jin ; Woolard, Kevin D ; 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. / Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Pathway Inhibits Differentiation of Glioblastoma-Initiating Cells. In: Cancer Cell. 2008 ; Vol. 13, No. 1. pp. 69-80.
@article{a98069ea4cbb4f13b7b55703639a08e8,
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 Woolard, {Kevin D} 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.}",
year = "2008",
month = "1",
day = "8",
doi = "10.1016/j.ccr.2007.12.005",
language = "English (US)",
volume = "13",
pages = "69--80",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Pathway Inhibits Differentiation of Glioblastoma-Initiating Cells

AU - Lee, Jeongwu

AU - Son, Myung Jin

AU - Woolard, Kevin D

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.

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.

KW - CELLCYCLE

KW - MOLNEURO

UR - http://www.scopus.com/inward/record.url?scp=37349067098&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37349067098&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2007.12.005

DO - 10.1016/j.ccr.2007.12.005

M3 - Article

C2 - 18167341

AN - SCOPUS:37349067098

VL - 13

SP - 69

EP - 80

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 1

ER -