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USP21 functions as an oncogenic regulator of the Mdm2-p53 axis in colorectal cancer

Zhongyu Wang1, Bo Yao1, Weiran He2

  • 1Department of Thoracic Surgery, The First Affiliated Hospital of USTC, National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Cell Death Discovery
|May 21, 2026
PubMed

Insights

The deubiquitinating enzyme USP21 stabilizes Mdm2, leading to the degradation of the tumor suppressor p53. This process accelerates colorectal cancer progression and is linked to poor patient survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The tumor suppressor p53 is crucial for preventing cancer.
  • Mdm2, a ubiquitin E3 ligase, inhibits p53 activity.
  • The regulatory network of Mdm2 and p53 is not fully understood.

Purpose of the Study:

  • To investigate the role of USP21 in the Mdm2-p53 regulatory network.
  • To elucidate the mechanism by which USP21 affects Mdm2 and p53.
  • To determine the functional and clinical significance of USP21 in colorectal cancer.

Main Methods:

  • Co-immunoprecipitation assays to assess protein interactions.
  • Western blotting to evaluate protein stability and ubiquitination levels.
  • Analysis of colorectal cancer patient data to correlate USP21 expression with survival.

Main Results:

  • USP21 physically interacts with Mdm2 and enhances its stability independently of its deubiquitinase activity.
  • USP21 acts as a scaffold, promoting the USP7-Mdm2 interaction.
  • USP21 overexpression leads to increased p53 ubiquitination and degradation, suppressing its tumor suppressive function and promoting colorectal cancer.
  • Elevated USP21 levels in colorectal tumors correlate with reduced patient survival, particularly in those with wild-type p53.

Conclusions:

  • USP21 is a key regulator of the Mdm2-p53 axis.
  • USP21 promotes colorectal cancer progression by inhibiting p53.
  • USP21 represents a potential therapeutic target in colorectal cancer.

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