DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation.
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.
Sun
Peng
P
Department of Neurology, The Johns Hopkins University School of Medicine and The Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205, USA.
Xia
Shuli
S
Lal
Bachchu
B
Eberhart
Charles G
CG
Quinones-Hinojosa
Alfredo
A
Maciaczyk
Jarek
J
Matsui
William
W
Dimeco
Francesco
F
Piccirillo
Sara M
SM
Vescovi
Angelo L
AL
Laterra
John
J
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
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