title: DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2.
abstract: Cancer stem-like cells represent poorly differentiated multipotent tumor-propagating cells that contribute disproportionately to therapeutic resistance and tumor recurrence. Transcriptional mechanisms that control the phenotypic conversion of tumor cells lacking tumor-propagating potential to tumor-propagating stem-like cells remain obscure. Here we show that the reprogramming transcription factors Oct4 and Sox2 induce glioblastoma cells to become stem-like and tumor-propagating via a mechanism involving direct DNA methyl transferase (DNMT) promoter transactivation, resulting in global DNA methylation- and DNMT-dependent downregulation of multiple microRNAs (miRNAs). We show that one such downregulated miRNA, miRNA-148a, inhibits glioblastoma cell stem-like properties and tumor-propagating potential. This study identifies a novel and targetable molecular circuit by which glioma cell stemness and tumor-propagating capacity are regulated.
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lopez-Bertoni
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Lal
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Li
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Caplan
authors.affiliation: Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Guerrero-Cázares
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Eberhart
authors.affiliation: Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Quiñones-Hinojosa
authors.affiliation: Institute of Reconstructive Neurobiology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany.|Department of Neurology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany.|Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Glas
authors.affiliation: Institute of Reconstructive Neurobiology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Scheffler
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Laterra
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000502:physiology*; D010641:Phenotype; D055748:SOXB1 Transcription Factors / Q000502:physiology*
chemical_list: C550570:MIRN148 microRNA, human; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D004248:DNA (Cytosine-5-)-Methyltransferases