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

Author

Listed:
  • Han-Tsang Wu

    (Research Center for Tumor Medical Science, Graduate Institutes of Biomedical Sciences and New Drug Development, China Medical University)

  • Yi-Chih Kuo

    (Research Center for Tumor Medical Science, Graduate Institutes of Biomedical Sciences and New Drug Development, China Medical University)

  • Jung-Jyh Hung

    (Institute of Clinical Medicine, National Yang-Ming University
    Taipei Veterans General Hospital)

  • Chi-Hung Huang

    (Taiwan Advance Biopharm (TABP), Inc., Xizhi city)

  • Wei-Yi Chen

    (Institute of Biochemistry & Molecular Biology, National Yang-Ming University)

  • Teh-Ying Chou

    (Institute of Clinical Medicine, National Yang-Ming University
    Taipei Veterans General Hospital)

  • Yeh Chen

    (Hungkuang University)

  • Yi-Ju Chen

    (Institute of Chemistry, Academia Sinica)

  • Yu-Ju Chen

    (Institute of Chemistry, Academia Sinica)

  • Wei-Chung Cheng

    (Research Center for Tumor Medical Science, Graduate Institutes of Biomedical Sciences and New Drug Development, China Medical University)

  • Shu-Chun Teng

    (Graduate Institute of Microbiology, College of Medicine, National Taiwan University)

  • Kou-Juey Wu

    (Research Center for Tumor Medical Science, Graduate Institutes of Biomedical Sciences and New Drug Development, China Medical University
    China Medical University Hospital)

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.

Suggested Citation

  • Han-Tsang Wu & Yi-Chih Kuo & Jung-Jyh Hung & Chi-Hung Huang & Wei-Yi Chen & Teh-Ying Chou & Yeh Chen & Yi-Ju Chen & Yu-Ju Chen & Wei-Chung Cheng & Shu-Chun Teng & Kou-Juey Wu, 2016. "K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression," Nature Communications, Nature, vol. 7(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13644
    DOI: 10.1038/ncomms13644
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