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

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 and Kou-Juey Wu ()
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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
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
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

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13644

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