REST is a Novel Prognostic Factor and Therapeutic Target for Medulloblastoma

• Authors: Pete Taylor, University of Texas; Jason Fangusaro, Northwestern University; Veena Rajaram, Northwestern University; Stewart Goldman, Northwestern University; Irene B. Helenowski, Northwestern University; Tobey MacDonald, Emory University; Martin Hasselblatt, University Hospital; Lars Riedemann, University Children's Hospital; Alvaro Laureano, University of Texas; Laureano Cooper, University of Texas; Vidya Gopalakrishnan, University of Texas
• Journal Title: Molecular Cancer Therapeutics
• Volume: Volume 11, Number 8
• Publisher: American Association for Cancer Research | 2012-08-01, Pages 1713-1723
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/1535-7163.MCT-11-0990
• Subjects: Health Sciences, Oncology; Health Sciences, Pathology; Biology, Neuroscience
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; HISTONE DEACETYLASE INHIBITORS; PRIMITIVE NEUROECTODERMAL TUMORS; RESTRICTIVE SILENCER FACTOR; SCF-BETA-TRCP; PEDIATRIC MEDULLOBLASTOMA; RECURRENT MEDULLOBLASTOMA; NEURONAL DIFFERENTIATION; MOLECULAR-MECHANISMS; RISK MEDULLOBLASTOMA; GENE-EXPRESSION

Abstract

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 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 weremeasured by immunohistochemistry and stratified into negative, low/ moderate- (+/++/+++), and high-REST (+++++) groups. Kaplan-Meier curves revealed that patients with high-REST tumors hadworse overall and event-free survival comparedwith patients withREST-negative orRESTlow tumors. Because histone deacetylases (HDAC) are required for REST-dependent repression of neurogenesis, weevaluateda panel ofHDACinhibitors(HDACI) for their effects ongrowth anddifferentiationof 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 HDACIsmay have therapeutic potential for patients with REST-positive tumors. This warrants further investigation.