title: Epigenetic modulation of a miR-296-5p:HMGA1 axis regulates Sox2 expression and glioblastoma stem cells.
abstract: Solid malignancies contain subsets of multipotent cells that grow as spheres and efficiently propagate tumors in xenograft models, reflecting a stem-like, self-renewing and tumor-propagating phenotype. These cancer 'stem cells (SCs)' have been shown to maintain tumor growth, contribute to resistance and drive tumor recurrence. Cancer cell stemness is dynamically influenced by epigenetic mechanisms and differentially regulated coding and noncoding RNAs. How these mechanisms specifically contribute to the generation and/or maintenance of cancer SCs remains unclear. This study identifies a novel epigenetically regulated circuit that integrates microRNA, chromatin remodeling and the reprogramming transcription factor Sox2 to regulate glioblastoma (GBM)-propagating SCs. We show that miR-296-5p expression is repressed in a DNA methylation-dependent manner under conditions that promote GBM cell stemness and that miR-296-5p inhibits GBM cell stemness and their capacity to self-renew as spheres and propagate glioma xenografts in vivo. We show that the chromatin remodeling protein HMGA1 functions as a downstream effector of these biological responses to miR-296-5p and regulates Sox2 expression, a master driver of cell stemness, by modifying chromatin architecture at the Sox2 promoter. These results show for the first time that miR-296-5p inhibits transcriptional mechanisms that support GBM SCs and identify a miR-296-5p:HMGA1:Sox2 axis as a novel regulator of GBM SCs and candidate pathway for targeting therapies directed at depleting tumors of their tumor-propagating stem cell subsets.
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.|Department of Neurology, The 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, The 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: N
authors.initials: N
authors.lastname: Michelson
authors.affiliation: Department of Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Guerrero-Cázares
authors.affiliation: Department of Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Quiñones-Hinojosa
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.|Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.|Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, MD, USA.|Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Laterra
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D025741:HMGA1a Protein / Q000235:genetics*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C549871:MIRN296 microRNA, human; D035683:MicroRNAs; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D025741:HMGA1a Protein