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(1-6). Here we studied three types of human medulloblastoma cells that express markers corresponding to different levels of neuronal differentiation. They express ed the neuronal repressor element 1 (RE1) silencing transcription factor/ne uron-restrictive silencer factor (REST/NRSF; refs. 7-10) at very high level s compared with either neuronal progenitor NTera2 (NT2) cells or fully diff erentiated human neuron teratocarcinoma (hNT cells). To counter the effect of REST/NRSF, we used a recombinant transcription factor, REST-VP16, constr ucted by replacing repressor domains of REST/NRSF with the activation domai n of viral protein (VP16). Transient expression of REST-VP16 in medulloblas toma cells was able to compete with the endogenous REST/NRSF for DNA bindin g 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, stimu late 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 t heir growth. Therefore, REST/NRSF may serve as a new target for therapeutic interventions for medulloblastoma through agents such as REST-VP16.