K63 polyubiquitinated HAUSP deubiquitinates HIF 1a and dictates H3K56 acetylation promoting hypoxia induced tumour progression
Intratumoural hypoxia induces HIF 1a and promotes tumour progression, metastasis and treatment resistance. HIF 1a stability is regulated by VHL E3 ligase mediated ubiquitin dependent degradation; however, the hypoxia regulated deubiquitinase that stabilizes HIF 1a has not been identified. Here we report that HAUSP (USP7) deubiquitinase deubiquitinates HIF 1a 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 1a binding reveals two motifs responsive to hypoxia. HectH9 is the E3 ligase for HAUSP and a prognostic marker together with HIF 1a. This report demonstrates that hypoxia induced K63 polyubiquitinated HAUSP deubiquitinates HIF 1a and causes CBP mediated H3K56 acetylation on HIF 1a target gene promoters to promote EMT/metastasis, further defining HAUSP as a therapeutic target in hypoxia induced tumour progression.
Nature communications