USP8 positively regulates hepatocellular carcinoma tumorigenesis and confers ferroptosis resistance through β-catenin stabilization

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic carcinoma, which is a growing public health problem worldwide. One of the main genetic alterations in HCC is the deregulated Wnt/β-catenin signaling, activation of β-catenin is associated with the progression of HCC. In the present study, we aimed to identify novel modulators in controlling β-catenin ubiquitination and stability. USP8 was overexpressed in HCC tissues and correlated with β-catenin protein level. High expression of USP8 indicated poor prognosis of HCC patients. USP8 depletion significantly decreased β-catenin protein level, β-catenin target genes expression and TOP-luciferase activity in HCC cells. Further mechanistic study revealed that the USP domain of USP8 interacted with the ARM domain of β-catenin. USP8 stabilized β-catenin protein via inhibiting K48-specific poly-ubiquitination process on β-catenin protein. In addition, USP8 depletion inhibited the proliferation, invasion and stemness of HCC cells and conferred ferroptosis resistance, which effects could be further rescued by β-catenin overexpression. In addition, the USP8 inhibitor DUB-IN-3 inhibited the aggressive phenotype and promoted ferroptosis of HCC cells through degradation of β-catenin. Thus, our study demonstrated that USP8 activated the Wnt/beta-catenin signaling through a post-translational mechanism of β-catenin. High expression of USP8 promoted the progression and inhibited ferroptosis of HCC. Targeting the USP8 may serve as a promising strategy for patients with HCC.

Paired transcriptomic analyses of atheromatous and control vessels reveal novel autophagy and immunoregulatory genes in peripheral artery disease

“…Downregulation of STAG1 in PAD would indicate loss of genomic stability and predisposing the genome to DNA damage. USP8 is important for endosomal trafficking in atherosclerosis and is induced in presence of growth arrest during cell-cell contact and is also important in RAS signaling and Wnt pathway regulation 20 . Top downregulated transcription factors comprised of FOXQ1(log2FC=-0.61, p<0.05) and E2F3 (log2FC=-0.61, p<0.05).…”

Bismuth Sulfide Nanoflowers Facilitated miR339 Delivery to Overcome Stemness and Radioresistance through Ubiquitin-Specific Peptidase 8 in Esophageal Cancer

“…We analyzed the putative target of miR339 using the TargetScan database and identified a binding site for miR339 in the 3′ untranslated region (3′-UTR) of USP8 (Figure A,B). USP8 is crucial for tumorgenesis, including DNA double-strand break response and stem cell maintenance. − USP8 facilitates BRIT1 deubiquitination and recruitment to DSB-flanking chromatin for subsequent timely DNA repair and preservation of chromatin stability . USP8 directly deubiquitates EPG5 and consolidates EPG5 and LC3 interaction to guard the autophagic flux in embryonic stem cells (ESCs) for stemness maintenance .…”

Ferroptosis resistance in cancer cells: nanoparticles for combination therapy as a solution

“…When expressed, it inhibits lipid peroxidation independently of the GPX4 pathway. Its upregulation has been shown to be mediated by the expression of the transcription factor ATF4 ( Tang J. et al, 2023 ). ASCL4 plays an important role in lipid peroxidation.…”