REST regulates oncogenic properties of glioblastoma stem cells.
Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. Although many GBM tumors are believed to be caused by self-renewing, glioblastoma-derived stem-like cells (GSCs), the mechanisms that regulate self-renewal and other oncogenic properties of GSCs are only now being unraveled. Here we showed that GSCs derived from GBM patient specimens express varying levels of the transcriptional repressor repressor element 1 silencing transcription factor (REST), suggesting heterogeneity across different GSC lines. Loss- and gain-of-function experiments indicated that REST maintains self-renewal of GSCs. High REST-expressing GSCs (HR-GSCs) produced tumors histopathologically distinct from those generated by low REST-expressing GSCs (LR-GSCs) in orthotopic mouse brain tumor models. Knockdown of REST in HR-GSCs resulted in increased survival in GSC-transplanted mice and produced tumors with higher apoptotic and lower invasive properties. Conversely, forced expression of exogenous REST in LR-GSCs produced decreased survival in mice and produced tumors with lower apoptotic and higher invasive properties, similar to HR-GSCs. Thus, based on our results, we propose that a novel function of REST is to maintain self-renewal and other oncogenic properties of GSCs and that REST can play a major role in mediating tumorigenicity in GBM.
Department of Genetics,The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mohamed M
MM
Kamal
Pratheesh
P
Sathyan
Sanjay K
SK
Singh
Pascal O
PO
Zinn
Anantha L
AL
Marisetty
Shoudan
S
Liang
Joy
J
Gumin
Hala Osman
HO
El-Mesallamy
Dima
D
Suki
Howard
H
Colman
Gregory N
GN
Fuller
Frederick F
FF
Lang
Sadhan
S
Majumder
D054392:Adipokines / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D000071451:Chitinase-3-Like Protein 1; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D037102:Lectins / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099229:RE1-Silencing Transcription Factor
D054392:Adipokines; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C084533:CHI3L1 protein, human; C527782:SOX2 protein, human