title: Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis.
abstract: Metastatic dissemination is the leading cause of death in cancer patients, which is particularly evident for high-risk sarcomas such as Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. Previous research identified a crucial role for YB-1 in the epithelial-to-mesenchymal transition (EMT) and metastasis of epithelial malignancies. Based on clinical data and two distinct animal models, we now report that YB-1 is also a major metastatic driver in high-risk sarcomas. Our data establish YB-1 as a critical regulator of hypoxia-inducible factor 1α (HIF1α) expression in sarcoma cells. YB-1 enhances HIF1α protein expression by directly binding to and activating translation of HIF1A messages. This leads to HIF1α-mediated sarcoma cell invasion and enhanced metastatic capacity in vivo, highlighting a translationally regulated YB-1-HIF1α axis in sarcoma metastasis.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Amal M
authors.initials: AM
authors.lastname: El-Naggar
authors.affiliation: Department of Pediatrics, IWK Health Centre, Halifax, NS B3K 6R8, Canada.
authors.forename: Chansey J
authors.initials: CJ
authors.lastname: Veinotte
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Laboratory for Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Thalkirchner Strasse 36, 80337 Munich, Germany.
authors.forename: Thomas G P
authors.initials: TG
authors.lastname: Grunewald
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Negri
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Syam Prakash
authors.initials: SP
authors.lastname: Somasekharan
authors.affiliation: Department of Pediatrics, IWK Health Centre, Halifax, NS B3K 6R8, Canada.
authors.forename: Dale P
authors.initials: DP
authors.lastname: Corkery
authors.affiliation: INSERM U830, Laboratoire de génétique et biologie des cancers, Institut Curie, 75248 Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Tirode
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Joan
authors.initials: J
authors.lastname: Mathers
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Debjit
authors.initials: D
authors.lastname: Khan
authors.affiliation: Department of Integrative Oncology, Radiation Biology Unit, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Alastair H
authors.initials: AH
authors.lastname: Kyle
authors.affiliation: Department of Integrative Oncology, Radiation Biology Unit, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Baker
authors.affiliation: Department of Integrative Oncology, Radiation Biology Unit, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: LePard
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: McKinney
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Shamil
authors.initials: S
authors.lastname: Hajee
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Integrative Oncology, Radiation Biology Unit, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Momir
authors.initials: M
authors.lastname: Bosiljcic
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Leprivier
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Tognon
authors.affiliation: Department of Integrative Oncology, Radiation Biology Unit, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Minchinton
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Integrative Oncology, Radiation Biology Unit, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Bennewith
authors.affiliation: INSERM U830, Laboratoire de génétique et biologie des cancers, Institut Curie, 75248 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
authors.forename: Graham
authors.initials: G
authors.lastname: Dellaire
authors.affiliation: Department of Pediatrics, IWK Health Centre, Halifax, NS B3K 6R8, Canada; Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; Department of Pediatrics, Dalhousie University, Halifax, NS B3H 4R2, Canada.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Berman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, BC V5Z 1L3, Canada. Electronic address: psor@mail.ubc.ca.
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
mesh_terms: D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014176:Protein Biosynthesis; D012509:Sarcoma / Q000235:genetics / Q000473:pathology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology; D051840:Y-Box-Binding Protein 1 / Q000502:physiology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human