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Nat Commun. 2016 Dec 9;7:13644. doi: 10.1038/ncomms13644.

K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression.

Author information

1
Research Center for Tumor Medical Science, Graduate Institutes of Biomedical Sciences and New Drug Development, China Medical University, Taichung 404, Taiwan.
2
Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan.
3
Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
4
Taiwan Advance Biopharm (TABP), Inc., Xizhi city, New Taipei City 221, Taiwan.
5
Institute of Biochemistry &Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
6
Department of Pathology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
7
Department of Biotechnology, Hungkuang University, Taichung 433, Taiwan.
8
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
9
Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
10
Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.

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.

PMID:
27934968
PMCID:
PMC5155157
DOI:
10.1038/ncomms13644
[Indexed for MEDLINE]
Free PMC Article

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