Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16.
Medulloblastoma, one of the most malignant pediatric brain tumors, is believed to arise from the undifferentiated external granule-layer cells in the cerebellum. It is a heterogeneous cancer, and the mechanism of tumorigenesis for the majority of types is unknown. Repressor element-1 silencing transcription/neuron-restrictive silencer factor (REST/NRSF) is a transcriptional repressor that can block transcription of a battery of neuronal differentiation genes by binding to a specific consensus DNA sequence present in their regulatory region. Previously, we found that some medulloblastoma cell lines express REST/NRSF at high levels compared with either neuronal progenitor cells or fully differentiated neurons. However, it is not known if REST/NRSF is indeed overexpressed in human medulloblastoma tumor specimens and in what frequency. Here, we did an immunohistochemical analysis of such tumor specimens using an anti-REST antibody. We show that among 21 human medulloblastoma tumors, 17 expressed REST/NRSF (6 strongly and 11 weakly). In contrast, adjacent normal cerebellum tissue sections and four of the tumor specimens did not express REST/NRSF, indicating that abnormal expression of REST/NRSF is observed in the majority of human medulloblastoma tumors. To determine whether countering REST/NRSF activity blocks tumorigenicity of medulloblastoma cells, especially in the intracranial (i.c.) environment, we found that adenovirus-mediated expression of REST-VP16, a recombinant transcription factor that can compete with REST/NRSF and activate REST/NRSF target genes instead of repressing them, blocked the i.c. tumorigenic potential of medulloblastoma cells and inhibited growth of established tumors in nude mice, suggesting that REST/NRSF may serve as a therapeutic target for medulloblastoma and that forced expression of neuronal differentiation genes in medulloblastoma cells through agents, such as REST-VP16, can interfere with their tumorigenicity.
Fuller
Gregory N
GN
Brain Tumor Center, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 11, Houston, TX 77030, USA.
Su
Xiaohua
X
Price
Roger E
RE
Cohen
Zvi R
ZR
Lang
Frederick F
FF
Sawaya
Raymond
R
Majumder
Sadhan
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005047:Etoposide / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009474:Neurons / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis*; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D000099229:RE1-Silencing Transcription Factor
D005047:Etoposide; D049452:Green Fluorescent Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor