title: YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells.
abstract: Postnatal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells of origin for the SHH-associated subgroup of medulloblastoma, is driven by Sonic hedgehog (Shh) and insulin-like growth factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is upregulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh subgroup of medulloblastoma in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and MBCs and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.
authors.affiliation: Department of Pediatric Oncology, Emory University, Atlanta, GA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dey
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.|Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Robitaille
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: M
authors.identifier: 0000-0002-9404-9993
authors.initials: M
authors.lastname: Remke
authors.affiliation: Department of Pediatric Oncology, Emory University, Atlanta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Maier
authors.affiliation: Department of Pediatric Oncology, Emory University, Atlanta, GA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Gregorieff
authors.affiliation: Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: J L
authors.initials: JL
authors.lastname: Wrana
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.|Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Angers
authors.affiliation: Department of Pediatric Oncology, Emory University, Atlanta, GA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Kenney
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002531:Cerebellum / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D058953:Neural Stem Cells / Q000473:pathology*; D015398:Signal Transduction; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; C035170:IGF2 protein, human; C509239:SHH protein, human; D051840:Y-Box-Binding Protein 1; D007335:Insulin-Like Growth Factor II