title: p300- and Myc-mediated regulation of glioblastoma multiforme cell differentiation.
abstract: Tumorigenic potential of glioblastoma multiforme (GBM) cells is, in part, attributable to their undifferentiated (neural stem cell-like) phenotype. Astrocytic differentiation of GBM cells is associated with transcriptional induction of Glial Fibrillary Acidic Protein (GFAP) and repression of Nestin, whereas the reciprocal transcription program operates in undifferentiated GBM cells. The molecular mechanisms underlying the regulation of these transcription programs remain elusive. Here, we show that the transcriptional co-activator p300 was expressed in GBM tumors and cell lines and acted as an activator of the GFAP gene and a repressor of the Nestin gene. On the other hand, Myc (formerly known as c-Myc overrode these p300 functions by repressing the GFAP gene and inducing the Nestin gene in GBM cells. Moreover, RNAi-mediated inhibition of p300 expression significantly enhanced the invasion potential of GBM cells in vitro. Taken together, these data suggest that dedifferentiated/undifferentiated GBM cells are more invasive than differentiated GBM cells. Because invasion is a major cause of GBM morbidity, differentiation therapy may improve the clinical outcome.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Sreejith P
authors.initials: SP
authors.lastname: Panicker
authors.affiliation: Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Baisakhi
authors.initials: B
authors.lastname: Raychaudhuri
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Tipps
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Tapati
authors.initials: T
authors.lastname: Mazumdar
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, BLSC 3319 Elm and Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: Asoke K
authors.initials: AK
authors.lastname: Mal
authors.affiliation: Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Palomo
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.|Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.|Department of Neurosurgery, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Vogelbaum
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.|Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.|Department of Pulmonary, Allergy and Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: S Jaharul
authors.initials: SJ
authors.lastname: Haque
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054337:Cell Dedifferentiation; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050881:E1A-Associated p300 Protein / Q000235:genetics* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D058953:Neural Stem Cells; D034622:RNA Interference; D014158:Transcription, Genetic
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human