The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells.
Medulloblastoma is the most malignant pediatric brain tumor. It is believed to originate from the undifferentiated external granule layer cells in the cerebellum, but the mechanism of tumorigenesis remains unknown. Here we studied three types of human medulloblastoma cells that express markers corresponding to different levels of neuronal differentiation. They expressed the neuronal repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF; refs. 7-10) at very high levels compared with either neuronal progenitor NTera2 (NT2) cells or fully differentiated human neuron teratocarcinoma (hNT cells). To counter the effect of REST/NRSF, we used a recombinant transcription factor, REST-VP16, constructed by replacing repressor domains of REST/NRSF with the activation domain of viral protein (VP16). Transient expression of REST-VP16 in medulloblastoma cells was able to compete with the endogenous REST/NRSF for DNA binding and stimulate neuronal promoters. High-efficiency expression of REST-VP16 mediated by adenovirus vectors (Ad.REST-VP16) in medulloblastoma cells was able to counter REST/NRSF-mediated repression of neuronal promoters, stimulate expression of endogenous neuronal genes and trigger apoptosis through the activation of caspase cascades. Furthermore, intratumoral injection of Ad.REST-VP16 in established medulloblastoma tumors in nude mice inhibited their growth. Therefore, REST/NRSF may serve as a new target for therapeutic interventions for medulloblastoma through agents such as REST-VP16.
Lawinger
P
P
Brain Tumor Center, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 316, Houston, Texas 77005, USA.
Venugopal
R
R
Guo
Z S
ZS
Immaneni
A
A
Sengupta
D
D
Lu
W
W
Rastelli
L
L
Marin Dias Carneiro
A
A
Levin
V
V
Fuller
G N
GN
Echelard
Y
Y
Majumder
S
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002528:Cerebellar Neoplasms / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000628:therapy; D009474:Neurons / Q000166:cytology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000627:therapeutic use; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D000099229:RE1-Silencing Transcription Factor
D017405:Herpes Simplex Virus Protein Vmw65; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor