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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / physiology
  • Gene Expression Regulation, Neoplastic
  • Histones / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Models, Molecular
  • Oxygen / metabolism*
  • Peptide Fragments
  • Promoter Regions, Genetic
  • Protein Conformation
  • Sialoglycoproteins
  • Tandem Mass Spectrometry
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Specific Peptidase 7 / genetics
  • Ubiquitin-Specific Peptidase 7 / metabolism*
  • Ubiquitination

Substances

  • Histones
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Peptide Fragments
  • Sialoglycoproteins
  • Tumor Suppressor Proteins
  • bone sialoprotein (35-62), human
  • HUWE1 protein, human
  • Ubiquitin-Protein Ligases
  • USP7 protein, human
  • Ubiquitin-Specific Peptidase 7
  • Oxygen