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Updated: Jul 4, 2025

Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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Purification of Ubiquitinated p53 Proteins from Mammalian Cells

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The P53-P21-RB1 pathway promotes BRD4 degradation in liver cancer through USP1

Neng Li1, Erlei Zhang2, Zhenyong Li1

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The Journal of Biological Chemistry
|February 3, 2024
PubMed

Insights

The tumor suppressor P53 degrades BRD4 by inhibiting USP1 in liver cancer. This P53-USP1-BRD4 axis reveals new therapeutic targets for liver cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Liver cancer is difficult to treat with conventional therapies.
  • BRD4 (bromodomain-containing protein 4) is overexpressed in many cancers, promoting tumor growth.
  • The mechanisms regulating BRD4 protein levels are not fully understood.

Purpose of the Study:

  • To investigate the relationship between BRD4 protein levels and the tumor suppressor P53 in liver cancer.
  • To elucidate the regulatory mechanisms controlling BRD4 protein stability.
  • To identify potential therapeutic strategies targeting the BRD4 pathway in liver cancer.

Main Methods:

  • Analysis of TCGA datasets for protein level correlations.
  • In vivo and in vitro experiments to study protein degradation and deubiquitination.
  • Cell proliferation assays and xenograft models to assess tumor growth.
  • Functional transcriptomic analysis to identify gene networks.

Main Results:

  • A strong negative correlation was found between P53 and BRD4 protein levels in liver cancer.
  • P53 promotes BRD4 degradation by indirectly repressing USP1 (ubiquitin-specific peptidase 1) transcription via the P21-RB1 pathway.
  • USP1 deubiquitinates and stabilizes BRD4, contributing to its pro-tumor role.
  • The USP1-BRD4 axis maintains the expression of key cancer-related genes.

Conclusions:

  • A novel P53-P21-RB1-USP1-BRD4 signaling axis regulating liver cancer progression was identified.
  • Targeting USP1 or BRD4 could be a viable therapeutic strategy for liver cancer.
  • Understanding this axis provides insights into overcoming therapeutic resistance in liver cancer.
Keywords:
BRD4CDKN1ATP53deubiquitinationliver cancer

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