1. Academic Validation
  2. The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis

The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis

  • Cell Commun Signal. 2023 Aug 9;21(1):198. doi: 10.1186/s12964-023-01220-2.
Jianing Tang 1 2 Guo Long 1 Xuanxuan Li 1 Ledu Zhou 1 Yangying Zhou 3 4 Zheyu Wu 5 6
Affiliations

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, 410008, Hunan, China.
  • 3 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. zhouyy423@163.com.
  • 4 Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. zhouyy423@163.com.
  • 5 Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. wzywhu2013@163.com.
  • 6 Department of Orthopedics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200000, China. wzywhu2013@163.com.
Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal human malignancies, and with quite limited treatment alternatives. The Proteasome is responsible for most of the protein degradation in eukaryotic cells and required for the maintenance of intracellular homeostasis. However, its potential role in HCC is largely unknown. In the current study, we identified eukaryotic translation initiation factor 3 subunit H (EIF3H), belonging to the JAB1/MPN/MOV34 (JAMM) superfamily, as a bona fide deubiquitylase of O-GlcNAc transferase (OGT) in HCC. We explored that EIF3H was positively associated with OGT in HCC and was related to the unfavorable prognosis. EIF3H could interact with, deubiquitylate, and stabilize OGT in a deubiquitylase-dependent manner. Specifically, EIF3H was associated with the GT domain of ERα via its JAB/MP domain, thus inhibiting the K48-linked ubiquitin chain on OGT. Besides, we demonstrated that the knockdown of EIF3H significantly reduced OGT protein expression, cell proliferation and invasion, and caused G1/S arrest of HCC. We also found that the deletion of EIF3H prompted Ferroptosis in HCC cells. Finally, the effects of EIF3H depletion could be reversed by further OGT overexpression, implying that the OGT status is indispensable for EIF3H function in HCC carcinogenesis. In summary, our study described the oncogenic function of EIF3H and revealed an interesting post-translational mechanism between EIF3H, OGT, and Ferroptosis in HCC. Targeting the EIF3H may be a promising approach in HCC. Video Abstract.

Keywords

Deubiquitination; EIF3H; Ferroptosis; Hepatocellular carcinoma; OGT.

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