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REST Regulates Oncogenic Properties of Glioblastoma Stem Cells.
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Publication types: Journal Article Publication Status: ppublish. Author contributions: M.M.K., P.S., S.K.S., P.O.Z., and A.L.M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; S.L.: conception and design, data analysis and interpretation, and manuscript writing; J.G. and D.S.: provision of study material or patients, collection and/or assembly of data, and data analysis and interpretation; H.O.E.: financial support and administrative support; H.C.: provision of study material or patients; G.N.F. and F.F.L.: conception and design, provision of study material or patients, collection and/or assembly of data, and data analysis and interpretation; S.M.: conception and design, financial support, administrative support, data analysis and interpretation, manuscript writing, and final approval of manuscript. M.M.K. and P.S. contributed equally to this article. S.K.S. and P.O.Z. contributed equally to this article.
Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. Although many GBM tumors are believed to be caused by self-renewing, glioblastoma-derived stem-like cells (GSCs), the mechanisms that regulate self-renewal and other oncogenic properties of GSCs are only now being unraveled. Here we showed that GSCs derived from GBM patient specimens express varying levels of the transcriptional repressor repressor element 1 silencing transcription factor (REST), suggesting heterogeneity across different GSC lines. Loss- and gain-of-function experiments indicated that REST maintains self-renewal of GSCs. High REST-expressing GSCs (HR-GSCs) produced tumors histopathologically distinct from those generated by low REST-expressing GSCs (LR-GSCs) in orthotopic mouse brain tumor models. Knockdown of REST in HR-GSCs resulted in increased survival in GSC-transplanted mice and produced tumors with higher apoptotic and lower invasive properties. Conversely, forced expression of exogenous REST in LR-GSCs produced decreased survival in mice and produced tumors with lower apoptotic and higher invasive properties, similar to HR-GSCs. Thus, based on our results, we propose that a novel function of REST is to maintain self-renewal and other oncogenic properties of GSCs and that REST can play a major role in mediating tumorigenicity in GBM. STEM CELLS 2012;30:405-414.
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