title: REST is a novel prognostic factor and therapeutic target for medulloblastoma.
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 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.
authors: Department of Pediatrics, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Pete
authors: P
authors: Taylor
authors: Department of Pediatrics, Children's Memorial Hospital, Northwestern University and the Feinberg School of Medicine, Chicago, IL, USA.
authors: Jason
authors: J
authors: Fangusaro
authors: Department of Pathology, Children's Memorial Hospital, Northwestern University and the Feinberg School of Medicine, Chicago, IL, USA.
authors: Veena
authors: V
authors: Rajaram
authors: Department of Pediatrics, Children's Memorial Hospital, Northwestern University and the Feinberg School of Medicine, Chicago, IL, USA.
authors: Stewart
authors: S
authors: Goldman
authors: Department of Preventive Medicine, Children's Memorial Hospital, Northwestern University and the Feinberg School of Medicine, Chicago, IL, USA.
authors: Irene B
authors: IB
authors: Helenowski
authors: Department of Pediatrics, Winship Cancer Institute. Emory University. Atlanta, GA, USA.
authors: Tobey
authors: T
authors: MacDonald
authors: Institute of Neuropathology, University Hospital. Munster, Germany.
authors: Martin
authors: M
authors: Hasselblatt
authors: Department of Pediatric Hematology and Oncology, University Children's Hospital, Munster, Germany.
authors: Lars
authors: L
authors: Riedemann
authors: Department of Pediatrics, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Alvaro
authors: A
authors: Laureano
authors: Department of Pediatrics, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Laurence
authors: L
authors: Cooper
authors: Department of Pediatrics, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.|Department of Molecular and Cellular Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Vidya
authors: V
authors: Gopalakrishnan
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000077337:Vorinostat; D000099229:RE1-Silencing Transcription Factor
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D012097:Repressor Proteins; D000077337:Vorinostat; D000099229:RE1-Silencing Transcription Factor