title: Regulation of hypoxia responses by flavin adenine dinucleotide-dependent modulation of HIF-1α protein stability.
abstract: Oxygen deprivation induces a range of cellular adaptive responses that enable to drive cancer progression. Here, we report that lysine-specific demethylase 1 (LSD1) upregulates hypoxia responses by demethylating RACK1 protein, a component of hypoxia-inducible factor (HIF) ubiquitination machinery, and consequently suppressing the oxygen-independent degradation of HIF-1α. This ability of LSD1 is attenuated during prolonged hypoxia, with a decrease in the cellular level of flavin adenine dinucleotide (FAD), a metabolic cofactor of LSD1, causing HIF-1α downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF-1α stability, indicating a rate-limiting role for FAD in LSD1-mediated HIF-1α regulation. Transcriptomic analyses of patient tissues show that the HIF-1 signature is highly correlated with the expression of LSD1 target genes as well as the enzymes of FAD biosynthetic pathway in triple-negative breast cancers, reflecting the significance of FAD-dependent LSD1 activity in cancer progression. Together, our findings provide a new insight into HIF-mediated hypoxia response regulation by coupling the FAD dependence of LSD1 activity to the regulation of HIF-1α stability.
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.|Department of Bioscience and Biotechnology, Chungnam National University, Daejeon, South Korea.
authors.forename: Suk-Jin
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea.
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Park
authors.affiliation: Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea.
authors.forename: Byul
authors.initials: B
authors.lastname: Moon
authors.affiliation: Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: An
authors.affiliation: Biomedical Omics Group, Korea Basic Science Institute, Cheongju, South Korea.
authors.forename: Ju Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Pfizer Global Research and Development, San Diego, CA, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Pfizer Global Research and Development, San Diego, CA, USA.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pfizer Global Research and Development, San Diego, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pocalyko
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Dong Chul
authors.initials: DC
authors.lastname: Lee
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Hyun Ahm
authors.initials: HA
authors.lastname: Sohn
authors.affiliation: Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Minho
authors.identifier: 0000-0003-0069-026X
authors.initials: M
authors.lastname: Kang
authors.affiliation: Biomedical Omics Group, Korea Basic Science Institute, Cheongju, South Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Bioscience and Biotechnology, Chungnam National University, Daejeon, South Korea.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea kpark@kribb.re.kr jungaekim@kribb.re.kr yeomyi@kribb.re.kr.|Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Kyung Chan
authors.identifier: 0000-0002-7730-9466
authors.initials: KC
authors.lastname: Park
authors.affiliation: Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea kpark@kribb.re.kr jungaekim@kribb.re.kr yeomyi@kribb.re.kr.|Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Jung-Ae
authors.identifier: 0000-0001-5485-4843
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea kpark@kribb.re.kr jungaekim@kribb.re.kr yeomyi@kribb.re.kr.|Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea.
authors.forename: Young Il
authors.identifier: 0000-0003-4279-805X
authors.initials: YI
authors.lastname: Yeom
mesh_terms: D015687:Cell Hypoxia; D005182:Flavin-Adenine Dinucleotide / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D054875:Ubiquitination
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D005182:Flavin-Adenine Dinucleotide; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: FAD biosynthesis; HIF‐1; LSD1; cancer; hypoxia