K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression
Open accessAbstract
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.
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Hypoxia plays an important role in triggering EMT by regulating HIFs.
“Hypoxia plays an important role in triggering EMT by regulating HIFs.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [83]
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References 68 · Cited by 129
- Authors
- Wu, H.-T., Kuo, Y.-C., Hung, J.-J., Huang, C.-H., Chen, W.-Y., Chou, T.-Y., Chen, Y., Chen, Y.-J., Chen, Y.-J., Cheng, W.-C., Teng, S.-C., & Wu, K.-J.
- Affiliations
- China Medical University (TW)
- Taipei Veterans General Hospital (TW)
- National Yang Ming University (TW)
- Institute of Chemistry, Academia Sinica (TW)
- National Taiwan University (TW)
- Corresponding author
- Wu, Kou-Juey
- ORCID
- Venue
- Nature Communications
- Published
- 2016-12-09
- Volume
- 7
- Issue
- 1
- Pages
- 13644-13644
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5155157
- OpenAlex
- W2560007524
- Cited by
- 129
- References
- 68
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 17 · 2023: 10 · 2022: 22 · 2021: 12 · 2020: 12 · 2019: 16 · 2018: 8 · 2017: 11
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Council (MOST 104-2745-B-039-001-ASP, MOST 105, NHRI-EX104-10230SI)
- Academia Sinica
- Ministry of Science and Technology, Taiwan (MOST105-2745-B039-001-ASP)
- National Health Research Institutes (MOST 104-2745-B-039-001-ASP, NHRI-EX104-10230SI, EX104)
- National Research Program for Biopharmaceuticals (MOST 105-)
- National Taiwan University
- Taipei Veterans General Hospital (MOST 104-2745-B-039-001-ASP, NHRI-EX104-10230SI)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- USP7, HIF-1α, K63-linked ubiquitination, deubiquitination, H3K56 acetylation, CBP, intratumoral hypoxia, tumor progression, metastasis, epithelial-mesenchymal transition, protein stability, therapeutic target
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Acetylation, Histones, Humans, Lung Neoplasms, Models, Molecular, Oxygen, Peptide Fragments, Promoter Regions, Genetic, Protein Conformation, Sialoglycoproteins, Gene Expression Regulation, Neoplastic, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit, Tandem Mass Spectrometry, Ubiquitination, Epithelial-Mesenchymal Transition
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