title: K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression.
abstract: Intratumoural hypoxia induces HIF-1α and promotes tumour progression, metastasis and treatment resistance. HIF-1α stability is regulated by VHL-E3 ligase-mediated ubiquitin-dependent degradation; however, the hypoxia-regulated deubiquitinase that stabilizes HIF-1α has not been identified. Here we report that HAUSP (USP7) deubiquitinase deubiquitinates HIF-1α to increase its stability, induce epithelial-mesenchymal transition and promote metastasis. Hypoxia induces K63-linked polyubiquitinated HAUSP at lysine 443 to enhance its functions. Knockdown of HAUSP decreases acetylation of histone 3 lysine 56 (H3K56Ac). K63-polyubiquitinated HAUSP interacts with a ubiquitin receptor CBP to specifically mediate H3K56 acetylation. ChIP-seq analysis of HAUSP and HIF-1α binding reveals two motifs responsive to hypoxia. HectH9 is the E3 ligase for HAUSP and a prognostic marker together with HIF-1α. This report demonstrates that hypoxia-induced K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and causes CBP-mediated H3K56 acetylation on HIF-1α target gene promoters to promote EMT/metastasis, further defining HAUSP as a therapeutic target in hypoxia-induced tumour progression.
authors.affiliation: Research Center for Tumor Medical Science, Graduate Institutes of Biomedical Sciences and New Drug Development, China Medical University, Taichung 404, Taiwan.
authors.forename: Han-Tsang
authors.initials: HT
authors.lastname: Wu
authors.affiliation: Research Center for Tumor Medical Science, Graduate Institutes of Biomedical Sciences and New Drug Development, China Medical University, Taichung 404, Taiwan.
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Kuo
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors.forename: Jung-Jyh
authors.initials: JJ
authors.lastname: Hung
authors.affiliation: Taiwan Advance Biopharm (TABP), Inc., Xizhi city, New Taipei City 221, Taiwan.
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Institute of Biochemistry &Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan.|Department of Pathology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors.forename: Teh-Ying
authors.initials: TY
authors.lastname: Chou
authors.affiliation: Department of Biotechnology, Hungkuang University, Taichung 433, Taiwan.
authors.forename: Yeh
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Research Center for Tumor Medical Science, Graduate Institutes of Biomedical Sciences and New Drug Development, China Medical University, Taichung 404, Taiwan.
authors.forename: Wei-Chung
authors.initials: WC
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Teng
authors.affiliation: Research Center for Tumor Medical Science, Graduate Institutes of Biomedical Sciences and New Drug Development, China Medical University, Taichung 404, Taiwan.|Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Kou-Juey
authors.initials: KJ
authors.lastname: Wu
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D010100:Oxygen / Q000378:metabolism*; D010446:Peptide Fragments; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D012795:Sialoglycoproteins; D053719:Tandem Mass Spectrometry; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010446:Peptide Fragments; D012795:Sialoglycoproteins; D025521:Tumor Suppressor Proteins; C571744:bone sialoprotein (35-62), human; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; C464569:USP7 protein, human; D000076084:Ubiquitin-Specific Peptidase 7; D010100:Oxygen