title: Epigenetic re-expression of HIF-2α suppresses soft tissue sarcoma growth.
abstract: In soft tissue sarcomas (STS), low intratumoural O2 (hypoxia) is a poor prognostic indicator. HIF-1α mediates key transcriptional responses to hypoxia, and promotes STS metastasis; however, the role of the related HIF-2α protein is unknown. Surprisingly, here we show that HIF-2α inhibits high-grade STS cell growth in vivo, as loss of HIF-2α promotes sarcoma proliferation and increases calcium and mTORC1 signalling in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. We find that most human STS have lower levels of EPAS1 (the gene encoding HIF-2α) expression relative to normal tissue. Many cancers, including STS, contain altered epigenetics, and our findings define an epigenetic mechanism whereby EPAS1 is silenced during sarcoma progression. The clinically approved HDAC inhibitor Vorinostat specifically increases HIF-2α, but not HIF-1α, accumulation in multiple STS subtypes. Vorinostat inhibits STS tumour growth, an effect ameliorated by HIF-2α deletion, implicating HIF-2α as a biomarker for Vorinostat efficacy in STS.
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Nakazawa
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.|Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: T S Karin
authors.initials: TS
authors.lastname: Eisinger-Mathason
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Navid
authors.initials: N
authors.lastname: Sadri
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ochocki
authors.affiliation: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Terence P F
authors.initials: TP
authors.lastname: Gade
authors.affiliation: Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ruchi K
authors.initials: RK
authors.lastname: Amin
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.|Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006614:Hindlimb; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008080:Liposarcoma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D000077337:Vorinostat; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D058570:TOR Serine-Threonine Kinases; D000077337:Vorinostat; D000099162:Endothelial PAS Domain-Containing Protein 1
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