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

Authors


  • Author contributions: P.S.: conception and design, collection/assembly of data, data analysis/interpretation, manuscript writing, final approval; S.X.: collection/assembly of data, data analysis/interpretation, final approval; B.L.: collection/assembly of data, data analysis/interpretation, final approval; C.E.: conception and design, final approval; A.Q.: provision of study material, final approval; J.M.: provision of study material, final approval; W.M.: collection/assembly of data, final approval; F.D.: provision of study material, final approval; S.P.: provision of study material, final approval; A.V.: provision of study material, final approval; J.L.: conception and design, collection/assembly of data, data analysis/interpretation, manuscript writing, final approval.

  • First published online in STEM CELLS EXPRESS April 9, 2009.

Abstract

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

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