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Neurospheres derived from glioblastoma (GBM) and other solid malignancies contain neoplastic stem‐like cells that efficiently propagate tumor growth and resist cytotoxic therapeutics. The primary objective of this study was to use histone‐modifying agents to elucidate mechanisms by which the phenotype and tumor‐promoting capacity of GBM‐derived neoplastic stem‐like cells are regulated. Using established GBM‐derived neurosphere lines and low passage primary GBM‐derived neurospheres, we show that histone deacetylase (HDAC) inhibitors inhibit growth, induce differentiation, and induce apoptosis of neoplastic neurosphere cells. A specific gene product induced by HDAC inhibition, Delta/Notch‐like epidermal growth factor‐related receptor (DNER), inhibited the growth of GBM‐derived neurospheres, induced their differentiation in vivo and in vitro, and inhibited their engraftment and growth as tumor xenografts. The differentiating and tumor suppressive effects of DNER, a noncanonical Notch ligand, contrast with the previously established tumor‐promoting effects of canonical Notch signaling in brain cancer stem‐like cells. Our findings are the first to implicate noncanonical Notch signaling in the regulation of neoplastic stem‐like cells and suggest novel neoplastic stem cell targeting treatment strategies for GBM and potentially other solid malignancies. STEM CELLS 2009;27:1473–1486

DNER , an Epigenetically Modulated Gene, Regulates Glioblastoma‐Derived Neurosphere Cell Differentiation and Tumor Propagation