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VE-822 upregulates the deubiquitinase OTUD1 to stabilize FHL1 to inhibit the progression of lung adenocarcinoma

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Abstract

Background

The deubiquitinase ovarian tumor domain-containing 1 (OTUD1) has been considered as a tumor suppressor in many tumors, but there is minimal research on the role of OTUD1 in lung adenocarcinoma (LUAD) pathogenesis.

Methods

Bioinformatics analyses and western blot were applied for investigating OTUD1 expression in lung cancer and the drug that upregulated OTUD1. Kaplan–Meier analysis with log-rank test was used for survival analyses. IP-MS and co-IP were performed for identifying potential protein interactions with OTUD1. In vitro and in vivo assays were used for exploring the function of OTUD1 during the progression of LUAD.

Results

OTUD1 was dramatically downregulated in tumors and cell lines of human lung cancer. OTUD1 inhibited proliferation and migration of lung cancer cells in vitro. Moreover, OTUD1 inhibited growth of xenografts in nude mice and formation of primary lung tumors in urethane-induced lung cancer model. Mechanistically, we showed that OTUD1 deubiquitinated and stabilized FHL1. Furthermore, we listed and identified VE-822 as a candidate agonist for OTUD1. VE-822 inhibited proliferation of lung adenocarcinoma both in vitro and in vivo.

Conclusion

These results indicated that the deubiquitinase OTUD1, which was upregulated by VE-822, inhibited the progression of LUAD in vitro and in vivo by deubiquitinating and stabilizing FHL1.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No.82100673, No. 82170642, No.81801923, No.81700558, No.81570570, No.81670575 and No.81070355), Program of HUST Academic Frontier Youth Team (2018QYTD02), and Pre-Research Fund for Free Innovation of Union Hospital, Huazhong University of Science and Technology (No. 02.03.2017-312, No.02.03.2017-59, and No.02.03.2018-126).

Funding

This study was supported by grants from the National Natural Science Foundation of China (No.82100673, No. 82170642, No.81801923, No.81700558, No.81570570, No.81670575 and No.81070355), Program of HUST Academic Frontier Youth Team (2018QYTD02), and Pre-Research Fund for Free Innovation of Union Hospital, Huazhong University of Science and Technology (No. 02.03.2017-312, No.02.03.2017-59, and No.02.03.2018-126).

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Author notes

  1. Qi Zhang and Jinglei Li contributed equally to this work.

Authors and Affiliations

  1. Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Qi Zhang, Jinglei Li & Jinxiang Zhang

  2. Department of Medical Genetics, Basic School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Zihan Chen & Hui Wang

  3. Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Ke Jiang & Ai Huang

  4. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Kunyu Yang, Fang Huang & Hui Wang

  5. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Xiaodong Zhang

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  1. Qi Zhang
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Contributions

J.Z., H.W. and Q.Z. supervised the project and revised the manuscript. Q.Z. designed the study and completed the analysis of the database results. J.L. drafted the manuscript and performed the animal experiments. Z.C. performed the in vitro experiments. K.J. and K.Y. provided samples of lung cancer patients. F.H. and A.H. revised the manuscript. X.Z. conducted the drug database analysis. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jinxiang Zhang or Hui Wang.

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This study is compliant with all relevant ethical regulations regarding animal research. All procedures and experiments involving animals were approved by the Institution Animal Use and Care Committee of Huazhong University of Science and Technology (IACUC number: 2980).

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Zhang, Q., Li, J., Chen, Z. et al. VE-822 upregulates the deubiquitinase OTUD1 to stabilize FHL1 to inhibit the progression of lung adenocarcinoma. Cell Oncol. 46, 1001–1014 (2023). https://doi.org/10.1007/s13402-023-00793-x

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