5978

REST

NRSF|XBR;RE1-silencing transcription factor;REST;RE1-silencing transcription factor

neural-restrictive silencer factor|neuron restrictive silencer factor|repressor binding to the X2 box

4q12

protein-coding

Medulloblastoma is a malignant pediatric brain tumor. Current treatment following patient stratification into standard and high-risk groups using clinical features has improved survival. However, a subset of patients with standard risk featureshave unanticipated aggressive disease, underscoring the need for a better understanding of tumor biology and the development of novel treatments. Poor differentiation, a hallmark of medulloblastomas is associated with elevated expression levels of the repressor of neuronal differentiation called repressor element 1-silencing transcription factor (REST). Here, we assessed whether elevated REST expression levels had prognostic significance and whether its pharmacologic manipulation would promote neurogenesis and block tumor cell growth. REST levels in patient tumors were measured by immunohistochemistry and stratified into negative, low/moderate- (+/++/+++), and high-REST (+++++) groups. Kaplan-Meier curves revealed that patients with high-REST tumors had worse overall and event-free survival compared with patients with REST-negative or REST-low tumors. Because histone deacetylases (HDAC) are required for REST-dependent repression of neurogenesis, we evaluated a panel of HDAC inhibitors (HDACI) for their effects on growth and differentiation of established and primary REST-positive cell lines. MS-275, trichostatin-A (TSA), valproic acid (VPA), and suberoylanilide hydroxamic acid (SAHA) upregulated expression of the REST-target neuronal differentiation gene, Syn1, suggesting a potential effect of these HDACIs on REST function. Interestingly, VPA and TSA substantially increased histone acetylation at the REST promoter and activated its transcription, whereas SAHA unexpectedly promoted its proteasomal degradation. A REST-dependent decrease in cell growth was also observed following SAHA treatment. Thus, our studies suggest that HDACIs may have therapeutic potential for patients with REST-positive tumors. This warrants further investigation.

Non-neuronal cells and undifferentiated neuronal progenitors express the neuron-restrictive silencer factor (NRSF), a silencer protein which represses neuronal gene transcription in these cell types. Neuroblastoma, a childhood tumor of neuroectodermal origin, shares some biological properties with neuronal progenitor cells and can acquire neuronal phenotypes in response to a variety ofagents, including cyclic AMP and staurosporine. We report here that NRSF mRNA content was markedly decreased in a human neuroblastoma cell line following differentiation induced by staurosporine plus cyclic AMP, with a concomitant increase in mRNA levels of synapsin I, whose expression is restricted to neuronal cell types. Our novel finding suggests that NRSF expression is related to an undifferentiated state and regarded as a biochemical marker of neuronal differentiation in neuroblastoma cells.