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Updated: Dec 28, 2025
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency
Yu-Shui Ma1,2, Xiao-Feng Wang3, Yun-Jie Zhang3
1Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Abstract:
Functional elimination of p53 is a common feature of a large percentage of human malignancies. Here, we report the development of a pharmacological strategy aimed at restoring p53 function and its use for targeted therapy in p53-deficient mice. Specific inhibition of deubiquitinases ubiquitin-specific peptidase 14 (USP14) resulted in durable tumor regressions of autochthonous lymphomas and sarcomas in p53-deficient mice without affecting normal tissues, and therapeutic response was correlated with an increase in the ubiquitination of constitutive photomorphogenesis 9 (COP9) signalosome subunit 5 (COPS5), a key negative regulatory effector for p53. Inhibition of USP14 resulted in durable tumor regression through COPS5 deubiquitilation and a p53-dependent and -independent regulation mechanism by USP14. This series highlights the utility of proteasome deubiquitinating activity inhibition as a novel treatment paradigm for p53-deficient cancers. In addition, it provides preliminary evidence that inhibition of USP14 resulted in durable tumor regression through COPS5 deubiquitilation and p53-dependent and -independent regulation mechanism by USP14. These findings suggest that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target for patients with p53 deficiency.
Insights
Inhibiting deubiquitinase USP14 restores tumor suppressor p53 function, leading to regressions in p53-deficient cancers. This targeted therapy approach offers a new strategy for treating these malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Loss of the tumor suppressor p53 is prevalent in many human cancers.
- Restoring p53 function is a critical therapeutic goal for p53-deficient malignancies.
Purpose of the Study:
- To develop a pharmacological strategy to restore p53 function in p53-deficient cancers.
- To investigate the therapeutic potential of inhibiting deubiquitinases for cancer treatment.
Main Methods:
- Targeted inhibition of ubiquitin-specific peptidase 14 (USP14) in p53-deficient mouse models.
- Assessment of tumor regression, tissue effects, and molecular mechanisms involving COPS5 ubiquitination.
- Evaluation of p53-dependent and -independent regulatory pathways.
Main Results:
- Specific USP14 inhibition led to durable regressions in lymphomas and sarcomas in p53-deficient mice without harming normal tissues.
- Therapeutic response correlated with increased ubiquitination of COPS5, a negative regulator of p53.
- USP14 inhibition demonstrated efficacy through COPS5 deubiquitilation via p53-dependent and -independent mechanisms.
Conclusions:
- Inhibition of proteasome deubiquitinating activity, specifically USP14, represents a novel therapeutic strategy for p53-deficient cancers.
- The deubiquitinating activity of the 19S regulatory particle is identified as a potential anticancer drug target for patients with p53 deficiency.
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