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USP38 functions as an oncoprotein by downregulating the p53 pathway through deubiquitination and stabilization of MDM2

Cell Death & Differentiation volume 32, pages 1128–1141 (2025)Cite this article

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Abstract

Dysregulation of the MDM2-p53 pathway is a commonly observed phenomenon in cancer, where overexpression or amplification of MDM2 leads to increased degradation of p53. This results in reduced levels of p53, leading to the loss of its tumor-suppressive functions. The study focused on investigating the role of Ubiquitin-specific protease 38 (USP38) in cancer and its interaction with the MDM2-p53 axis. We revealed that USP38 positively correlates with MDM2 and negatively correlates with p53 expression. Mechanistically, USP38 directly binds to MDM2, functioning as a deubiquitinating enzyme (DUB) to stabilize MDM2 and suppress p53 expression. Knockout of USP38 hindered cancer cell proliferation, migration, and invasion, and enhanced apoptosis. Moreover, USP38 deficiency increased sensitivity to chemotherapy drugs and promoted ferroptosis in gastric and breast cancer cell lines. Importantly, these effects were found to be dependent on p53, as the downregulation of p53 reversed the phenotypic changes induced by USP38 knockout. These findings shed light on the oncogenic role of USP38 by modulating the MDM2-p53 axis, providing valuable insights into the molecular mechanisms of USP38 in cancer and potential therapeutic strategies for gastric and breast cancer.

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Fig. 1: USP38 specially interacts with MDM2, but not p53.
Fig. 2: USP38 modulates the stability of MDM2 and p53 by deubiquitinating MDM2, influencing cellular sensitivity to chemotherapy drugs.
Fig. 3: USP38 regulates cell growth and apoptosis.
Fig. 4: USP38 enhances the migration and invasion of carcinoma cells.
Fig. 5: USP38 is involved in regulating cellular ferroptosis.
Fig. 6: USP38 regulates cell phenotypes and ferroptosis in a p53 dependent manner.
Fig. 7: Expression and Prognostic Value of USP38 in STAD.

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Data availability

Information on experimental reagents and primer sequences can be found in the Supplementary Tables. All other data are available from the corresponding authors upon request.

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Funding

This work was in part supported by the National Natural Science Foundation of China (No. 81872260, 82172938 to PZZ), the Shanghai Natural Science Foundation (No. 21ZR1450300 to XPL), the National Key Clinical Specialties-Pathology (No. YWP2023-001 to YYH).

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Author notes

  1. These authors contributed equally: Shanyu Zhao, Xiaoli Liu.

Authors and Affiliations

  1. Department of Pathology, School of Basic Medical Sciences, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China

    Shanyu Zhao, Xiaoli Liu, Zitao Jian, Xiuping Liu & Pingzhao Zhang

  2. Department of Pathology, School of Basic Medical Sciences, Dali University, Yunnan, China

    Shanyu Zhao

  3. Department of Pathology, General Hospital of Ningxia Medical University, Ningxia Hui Autonomous Region, China

    Xiaoli Liu

  4. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China

    Rongkui Luo, Chen Xu & Yingyong Hou

  5. Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China

    Pingzhao Zhang

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  1. Shanyu Zhao
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  2. Xiaoli Liu
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Contributions

PZZ and XPL conceived the study. SYZ, XLL, RKL, ZTJ, CX performed the experiments and data analyses. PZZ, XPL, YYH analyzed and interpreted the data. PZZ and SYZ wrote the manuscript.

Corresponding authors

Correspondence to Yingyong Hou, Xiuping Liu or Pingzhao Zhang.

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This study involved human subjects and animal experiments and was approved by the Ethics Review Committee of Fudan University.

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Zhao, S., Liu, X., Luo, R. et al. USP38 functions as an oncoprotein by downregulating the p53 pathway through deubiquitination and stabilization of MDM2. Cell Death Differ 32, 1128–1141 (2025). https://doi.org/10.1038/s41418-025-01462-2

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