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Deubiquitinating enzyme Josephin-2 stabilizes PHGDH to promote a cancer stem cell phenotype in hepatocellular carcinoma

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Abstract

Background

Deubiquitinating enzymes (DUBs) have been shown to be possible targets for hepatocellular carcinoma (HCC) treatment.

Objective

This study was designed to reveal the effect and underlying mechanism of Josephin-2, a relatively newly defined DUB, in HCC progression.

Methods

SNU-387 and PLC/PRF/5 cells were used for in vitro functional assays. The levels of Josephin-2 and phosphoglycerate dehydrogenase (PHGDH) were determined using RT-qPCR and western blotting. Cell proliferation, migration and invasion were assessed by CCK-8, colony formation and Transwell. Spheroid-forming assay was performed to assess the cancer stem cell (CSC)-phenotype of HCC cells. A xenograft mice model was applied to verify the effect of Josephin-2 on HCC cell growth in vivo.

Results

Herein, we showed that Josephin-2 expression was negatively correlated with HCC patient survival in data from the online database. Cell experiments indicated that knockdown of Josephin-2 attenuated HCC cell malignant biological behaviors. Besides, Josephin-2 silencing also decreased the spheroid-formation while inhibited the expression of CSC biomarkers (CD133, OCT4, SOX2 and EpCAM) in HCC cells. Mechanistically, Josephin-2 had a deubiquitinating activity towards the regulation of PHGDH protein, the rate-limiting enzyme in the first step of serine biosynthesis pathway. Depletion of Josephin-2 enhanced the ubiquitination degradation of PHGDH and ultimately inhibited the proliferation and CSC-phenotype of HCC in vitro and in vivo.

Conclusion

Our work uncovered the regulatory effects of Josephin-2 on PHGDH protein stability and profiled its contribution in HCC malignant progression, which might provide a potential therapeutic target for HCC.

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Acknowledgements

This research was funded by the Youth Cultivation Fund of The First Affiliated Hospital of Xinxiang Medical University (No. QN-2021-B05), the Start-up Fund for Doctoral Research Project of The First Affiliated Hospital of Xinxiang Medical University (No. 11023) and the Joint Construction Project of Henan Medical Science and Technology Research Plan (No. LHGJ20200495 and LHGJ20220601).

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Authors and Affiliations

  1. The First Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, Henan Province, China

    Ying Wang, Lu-Hao Li & Xiao-Wei Dang

  2. Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, China

    Ying Wang, Ze-Xin Li, Jian-Guo Wang & Wen-Long Shen

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  1. Ying Wang
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  2. Ze-Xin Li
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  3. Jian-Guo Wang
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  4. Lu-Hao Li
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Correspondence to Xiao-Wei Dang.

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All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethical approval

The animal experiment in this study was approved by the ethics committee of The First Affiliated Hospital of Xinxiang Medical University (EC-021-056).

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Wang, Y., Li, ZX., Wang, JG. et al. Deubiquitinating enzyme Josephin-2 stabilizes PHGDH to promote a cancer stem cell phenotype in hepatocellular carcinoma. Genes Genom 45, 215–224 (2023). https://doi.org/10.1007/s13258-022-01356-4

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