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OTUB1 antagonizes TRIM21 to induce deubiquitination of SPHK1 and promote the progression of hepatocellular carcinoma

Oncogene volume 44, pages 3985–3998 (2025)Cite this article

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Abstract

SPHK1 is critical for maintaining cellular lipid balance. Aberrant expression of SPHK1 aggravates malignancy of tumor through multiple signaling pathways. Here, we report a novel regulatory mechanism in ubiquitination of SPHK1. It is demonstrated that TRIM21 facilitates SPHK1 degradation via promoting K48-linked polyubiquitination. OTUB1 prohibits the TRIM21-induced ubiquitination of SPHK1 to maintain its high expression level. These findings define a new insight into the ubiquitination regulatory axis of SPHK1 and demonstrate that OTUB1-mediated SPHK1 stabilization facilitates proliferation and migration of HCC cells.

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Fig. 1: SPHK1 is upregulated in HCC and serves as a risk factor for poor prognosis.
Fig. 2: SPHK1 physically interacts with OTUB1 in HCC.
Fig. 3: OTUB1 stabilizes the expression of SPHPK1 protein.
Fig. 4: OTUB1 stabilizes the expression of SPHK1 through deubiquitination.
Fig. 5: OTUB1 accelerates HCC proliferation by upregulating SPHK1.
Fig. 6: SPHK1 and OTUB1 regulate the metastasis of HCC.
Fig. 7: SPHK1 protein level in HCC cells is regulated by OTUB1 and TRIM21.
Fig. 8: OTUB1 and TRIM21 correlate with SPHK1 and predicts poor prognosis of HCC patients.

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Data availability

The datasets examined in this study can be obtained from the corresponding author upon reasonable request.

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Funding

This study was partially funded by the Foundation of the Department of Science and Technology of Liaoning Province [grant number 2022-BS-140].

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Author notes

  1. These authors contributed equally: Chen Sun, Shuang Cai, Jun Yang.

Authors and Affiliations

  1. Department of Interventional Radiology, Shengjing Hospital of China Medical University, Shenyang, China

    Chen Sun, Mingyang Du, Wei Sun & Hongyuan Liang

  2. Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China

    Shuang Cai

  3. Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China

    Jun Yang

  4. Department of Hepatobiliary Surgery and Organ Transplantation, First Hospital of China Medical University, Shenyang, China

    Qi Pan

  5. Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing, China

    Yutao Wang

  6. Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China

    Ming Bai

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Contributions

Chen Sun: writing – review & editing, writing – original draft, visualization, validation, project administration, methodology, investigation, funding acquisition, formal analysis, conceptualization. Shuang Cai: writing – review & editing, writing – original draft, validation, supervision, resources, project administration, methodology, investigation, conceptualization. Jun Yang: writing – review & editing, writing – original draft, validation, supervision, resources, project administration, methodology, investigation, conceptualization. Mingyang Du: writing – review & editing, supervision, methodology. Qi Pan: writing – review & editing, supervision, methodology. Yutao Wang: writing – review & editing, supervision, project administration, conceptualization. Wei Sun: writing – review & editing, supervision, project administration, conceptualization. Ming Bai: writing – review & editing, supervision, project administration, conceptualization. Hongyuan Liang: writing – review & editing, supervision, project administration, conceptualization.

Corresponding authors

Correspondence to Yutao Wang, Wei Sun, Ming Bai or Hongyuan Liang.

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Sun, C., Cai, S., Yang, J. et al. OTUB1 antagonizes TRIM21 to induce deubiquitination of SPHK1 and promote the progression of hepatocellular carcinoma. Oncogene 44, 3985–3998 (2025). https://doi.org/10.1038/s41388-025-03556-0

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