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

  • Cell Death Dis. 2023 Jun 13;14(6):360. doi: 10.1038/s41419-023-05747-7.
Jianing Tang  1  2 ,  Guo Long  1  2 ,  Liang Xiao  3  4 ,  Ledu Zhou  5  6
Affiliations
  • 1. Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 3. Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. [email protected].
  • 4. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. [email protected].
  • 5. Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. [email protected].
  • 6. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. [email protected].
PMID: 37311739 DOI: 10.1038/s41419-023-05747-7
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.

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