2. Academic Validation
  3. UCHL3 inhibits ferroptosis by stabilizing β-catenin and maintains stem-like properties of hepatocellular carcinoma cells

UCHL3 inhibits ferroptosis by stabilizing β-catenin and maintains stem-like properties of hepatocellular carcinoma cells

  • Free Radic Biol Med. 2023 Dec 12:212:162-173. doi: 10.1016/j.freeradbiomed.2023.11.030.
Guo Long 1,  Zheyu Wu 2,  Dong Wang 3,  Xingyu Mi 1,  Kuan Hu 4,  Ledu Zhou 5,  Jianing Tang 6
Affiliations

Affiliations

  • 1 Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 2 Department of Orthopedics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200000, China.
  • 3 Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
  • 4 Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. Electronic address: kuan.hu@csu.edu.cn.
  • 5 Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. Electronic address: zhould@csu.edu.cn.
  • 6 Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. Electronic address: tangjn@csu.edu.cn.
PMID: 38092274 DOI: 10.1016/j.freeradbiomed.2023.11.030
Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic liver Cancer. Dysregulated Wnt/β-catenin activation is closely related to the progression of Cancer. Nevertheless, the mechanism that sustains the abnormal expression of β-catenin in HCC has yet to be identified. In this study, we find that UCHL3 is overexpressed in HCC tissues and correlated with β-catenin protein level. High expression of UCHL3 is associated with poor prognosis. UCHL3 knockdown markedly reduces the protein level of β-catenin in HCC cells. TOP-luciferase activity and β-catenin target genes expression are also decreased upon UCHL3 depletion. We find that the ARM domain of β-catenin is required for the interaction with UCHL3. UCHL3 increases β-catenin protein stability via removing K48-specific poly-ubiquitin chains from β-catenin protein. Furthermore, the depletion of UCHL3 induces Ferroptosis and hinders the growth, invasion, and stem cell properties of HCC cells. These impacts could be restored by the overexpression of β-catenin. In addition, the UCHL3 inhibitor TCID inhibits the aggressive phenotype of HCC through the degradation of β-catenin. In general, our results indicates that UCHL3 increases the stability of β-catenin, which in turn facilitates tumorigenesis of HCC, suggesting that targeting UCHL3 may be a promising approach for the treatment of HCC.

Keywords

Hepatocellular carcinoma; Stabilization; UCHL3; Ubiquitination; β-catenin.

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