Preclinical Development REST Is a Novel Prognostic Factor and Therapeutic Target for Medulloblastoma

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 features have 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 assessedwhether elevatedREST expression levels had prognostic significance and whether its pharmacologic manipulation would promote neurogenesis and block tumor cell growth.REST levels inpatient tumorsweremeasuredby immunohistochemistry and stratified into negative, low/ moderate(þ/þþ/þþþ), and high-REST (þþþþþ) groups. Kaplan–Meier curves revealed that patients with high-REST tumorshadworseoverall andevent-free survival comparedwithpatientswithREST-negativeorRESTlow tumors. Because histone deacetylases (HDAC) are required for REST-dependent repression of neurogenesis, weevaluatedapanelofHDACinhibitors (HDACI) for their effects ongrowthanddifferentiationof establishedand 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 HDACIsmay have therapeutic potential for patients with REST-positive tumors. This warrants further investigation. Mol Cancer Ther; 11(8); 1713–23. 2012 AACR.