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

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.

Sp1‐mediated epigenetic dysregulation dictates HDAC inhibitor susceptibility of HER2‐overexpressing breast cancer

“…Histone acetylation regulates gene expression by removing the positive charge on histones and decreasing histone–DNA interaction, thereby transforming the chromatin into a more relaxed structure required for transcription and increasing its accessibility to Pol II . Recent studies show that H3K56 acetylation plays important roles in nucleosome unwrapping and gene expression by dictating the accessibility of DNA to nucleases and transcription factors . The homeostasis of histone acetylation and deacetylation is maintained by several classes of histone acetyltransferases (HATs) and HDACs .…”

“…6,41 Recent studies show that H3K56 acetylation plays important roles in nucleosome unwrapping and gene expression by dictating the accessibility of DNA to nucleases and transcription factors. 42,43 The homeostasis of histone acetylation and deacetylation is maintained by several classes of histone acetyltransferases (HATs) and HDACs. 41,44 Nevertheless, the histone acetylation status of an individual gene is largely determined by the DNA-binding proteins or essential components of epigenetic modification complexes that recruit HATs and/or HDACs to specific genomic loci.…”

Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3

“…Thus, hypoxia could regulate PHF8 through USP7. Beyond, USP7 deubiquitinates and stabilizes HIF1α, PHF8 could regulate HIF1α through USP7 [49]. These hypotheses need to be tested in prostate cancer cells.…”

Regulation of miRNA Biogenesis and Histone Modification by K63-Polyubiquitinated DDX17 Controls Cancer Stem-like Features

“…RNA purification, cDNA synthesis, and quantitative real-time PCR analysis were performed as described previously (24). For miRNA, RNA was extracted by TRIzol (Invitrogen).…”

“…Cells were cross-linked with 1% formaldehyde for 10 minutes and stopped by glycine to a final concentration of 0.125 mol/L (24). Fixed cells were washed twice with Tris buffered saline (20 mmol/L Tris, pH 7.5, 150 mmol/L NaCl) and harvested in 5 mL of SDS buffer (50 mmol/L Tris, pH 8.0, 0.5% SDS, 100 mmol/L NaCL, 5 mmol/L EDTA, and protease inhibitors).…”