title: NQO1 inhibits proteasome-mediated degradation of HIF-1α.
abstract: Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate that NQO1 directly binds to the oxygen-dependent domain of HIF-1α and inhibits the proteasome-mediated degradation of HIF-1α by preventing PHDs from interacting with HIF-1α. NQO1 knockdown in human colorectal and breast cancer cell lines suppresses HIF-1 signalling and tumour growth. Consistent with this pro-tumorigenic function for NQO1, high NQO1 expression levels correlate with increased HIF-1α expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1α stability in cancers.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea.|Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
authors.forename: Eun-Taex
authors.initials: ET
authors.lastname: Oh
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75080, USA.
authors.forename: Jung-Whan
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, Inha University, Incheon 400-712, Republic of Korea.
authors.forename: Joon Mee
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea.|Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
authors.forename: Jae-Seon
authors.identifier: http://orcid.org/0000-0001-6002-5267
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea.|Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75080, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Goodwin
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75080, USA.
authors.forename: Robin J
authors.identifier: http://orcid.org/0000-0001-5542-6234
authors.initials: RJ
authors.lastname: Ruthenborg
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Myung Gu
authors.initials: MG
authors.lastname: Jung
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Hae-June
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of Polymer Science and Engineering, Inha University, Incheon 22212, Republic of Korea.
authors.forename: Chulhee
authors.initials: C
authors.lastname: Kim
authors.affiliation: Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.|Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
authors.forename: Heon Joo
authors.initials: HJ
authors.lastname: Park
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055550:Protein Stability
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen