title: DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation.
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.
authors: Department of Neurology, The Johns Hopkins University School of Medicine and The Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205, USA.
authors: Peng
authors: P
authors: Sun
authors: Shuli
authors: S
authors: Xia
authors: Bachchu
authors: B
authors: Lal
authors: Charles G
authors: CG
authors: Eberhart
authors: Alfredo
authors: A
authors: Quinones-Hinojosa
authors: Jarek
authors: J
authors: Maciaczyk
authors: William
authors: W
authors: Matsui
authors: Francesco
authors: F
authors: Dimeco
authors: Sara M
authors: SM
authors: Piccirillo
authors: Angelo L
authors: AL
authors: Vescovi
authors: John
authors: J
authors: Laterra
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000473:pathology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; C462501:DNER protein, human; D056572:Histone Deacetylase Inhibitors; D009419:Nerve Tissue Proteins; D011725:Pyridines; D011956:Receptors, Cell Surface; C118739:entinostat; D006655:Histone Deacetylases