Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells.
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.
Lee
Jeongwu
J
Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Son
Myung Jin
MJ
Woolard
Kevin
K
Donin
Nicholas M
NM
Li
Aiguo
A
Cheng
Chui H
CH
Kotliarova
Svetlana
S
Kotliarov
Yuri
Y
Walling
Jennifer
J
Ahn
Susie
S
Kim
Misuk
M
Totonchy
Mariam
M
Cusack
Thomas
T
Ene
Chibawanye
C
Ma
Hilary
H
Su
Qin
Q
Zenklusen
Jean Claude
JC
Zhang
Wei
W
Maric
Dragan
D
Fine
Howard A
HA
D000818:Animals; D001253:Astrocytes / Q000473:pathology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D052005:Bone Morphogenetic Protein Receptors, Type I