title: Hypoxia-induced SUMOylation of E3 ligase HAF determines specific activation of HIF2 in clear-cell renal cell carcinoma.
abstract: Clear-cell renal cell cancer (CRCC) is initiated typically by loss of the tumor-suppressor VHL, driving constitutive activation of hypoxia-inducible factor-1 (HIF1) and HIF2. However, whereas HIF1 has a tumor-suppressor role, HIF2 plays a distinct role in driving CRCC. In this study, we show that the HIF1α E3 ligase hypoxia-associated factor (HAF) complexes with HIF2α at DNA to promote HIF2-dependent transcription through a mechanism relying upon HAF SUMOylation. HAF SUMOylation was induced by hypoxia, whereas HAF-mediated HIF1α degradation was SUMOylation independent. HAF overexpression in mice increased CRCC growth and metastasis. Clinically, HAF overexpression was associated with poor prognosis. Taken together, our results show that HAF is a specific mediator of HIF2 activation that is critical for CRCC development and morbidity.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California. mkoh@sanfordburnham.org.
authors.forename: Mei Yee
authors.initials: MY
authors.lastname: Koh
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vuvi
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Lemos
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Galina
authors.initials: G
authors.lastname: Kiriakova
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mena
authors.initials: M
authors.lastname: Abdelmelek
authors.affiliation: Department of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, Arizona.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Department of GU Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jose
authors.initials: J
authors.lastname: Karam
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Federico A
authors.initials: FA
authors.lastname: Monzon
authors.affiliation: Department of GU Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D017411:Ribonucleoproteins, Small Nuclear; D058207:Sumoylation; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017411:Ribonucleoproteins, Small Nuclear; D015534:Trans-Activators; D044767:Ubiquitin-Protein Ligases; D000099162:Endothelial PAS Domain-Containing Protein 1; C431323:SART1 protein, human; C411898:Sart1 protein, mouse