USP21/YBX1/HIF1-α promotes the progression of prostate cancer

Sep 23, 2026

Prostate cancer remains a prevalent male malignancy, and the precise contribution of the deubiquitinating enzyme USP21 to disease progression is not established. This work presents a comprehensive analysis identifying USP21 as a key oncogenic driver. USP21 expression was assessed in tissues and cell lines, and USP21 function was tested in organoids and in vitro/in vivo models. Mechanistically, USP21 targets YBX1 to enhance HIF1-α signaling, and pharmacologic inhibition with Bay-805 suppressed progression.

LanguageEnglish

CategoryHealthcare

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Pages17

Reading Time43 min

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Abstract

Methods

Results

Conclusions

Introduction

Gu et al. Journal of Translational Medicine (2025) 23:1164 [https://doi.org/10.1186/s12967-025-07199-3](https://doi.org/10.1186/s12967-025-07199-3) Journal of Translational Medicine RESEARCH Open Access USP21/YBX1/HIF1-α promotes the progression of prostate cancer Zhuoran Gu 1,2†, Libin Zou 1,2†, Cheng Jiang 1,2†, Feng Qi3†, Dan Huang 1,2,4, Ji Liu 1,2, Yadong Guo 1,2, Shiyu Mao 1,2, Junfeng Zhang 1,2, Yue Zhang5, Donghui Shi6, Jiang Geng 1,2*, Yifan Chen 1,2*, Wentao Zhang 1,2* and Xudong Yao 1,2* Abstract Background Prostate cancer (PCa) is one of the prevalent cancers in men. Although deubiquitinating enzymes are implicated in tumorigenesis and progression, the specific role of ubiquitin specific peptidase 21 (USP21) in PCa remains unclear. This study provides the first comprehensive analysis of USP21 as a key oncogene driving PCa progression. Methods Prognosis-related deubiquitinating enzymes in PCa were initially identified through PCa cohorts from TCGA and GEO databases, followed by experimental validation. USP21 expression in PCa tissues and cell lines using tissue microarray immunohistochemistry, western blotting, and RT-qPCR. The biological functions of USP21 were evaluated through patient-derived organoids, in vitro and in vivo experiments. USP21 substrate proteins were identified by co-immunoprecipitation (Co-IP) coupled with mass spectrometry, revealing Y-box binding protein 1 (YBX1) as the primary target. YBX1 transcriptional activity was quantified using dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) . The effect of USP21 inhibition was evaluated using the USP21-targeted inhibitor Bay-805 in PCa cells. Results USP21 is upregulated in PCa and correlates with poor prognosis. Functional assays demonstrated that USP21 knockdown significantly inhibited PCa cells proliferation, migration, and invasion. RNA-sequencing further revealed that USP21 modulates the HIF1 signaling pathway. Mechanistically, USP21 deubiquitinates and stabilizes YBX1, which in turn enhances HIF1A (encoding HIF1-α) transcription. Notably, pharmacological inhibition of USP21 with Bay-805 suppressed PCa progression, highlighting its therapeutic potential. Conclusions USP21 promotes PCa malignancy by interacting with YBX1 to upregulate HIF1-α expression. These findings suggest Bay-805 as a promising therapeutic candidate for PCa. †Zhuoran Gu, Libin Zou, Cheng Jiang, Feng Qi contributed equally to this work. *Correspondence: Jiang Geng [gengjiangsn@sina.com](gengjiangsn@sina.com)[ ](gengjiangsn@sina.com)Yifan Chen[chenyifan555@yeah.net](chenyifan555@yeah.net)[ ](chenyifan555@yeah.net)Wentao Zhang [zhangwentao98@163.com](zhangwentao98@163.com)[ ](zhangwentao98@163.com)Xudong Yao [yxd@tongji.edu.cn](yxd@tongji.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/. Gu et al. Journal of Translational Medicine (2

FAQs

What is the main objective of the study on USP21 in prostate cancer?

To determine how USP21 contributes to prostate cancer progression and clarify its underlying mechanism.

How was USP21 expression and function evaluated in this research?

USP21 levels were measured in PCa tissues and cell lines using immunohistochemistry, western blotting, and RT-qPCR, and its functions were tested with patient-derived organoids and in vitro/in vivo experiments.

What mechanism links USP21 to HIF1-α signaling?

USP21 deubiquitinates and stabilizes YBX1, which increases HIF1A transcription and thereby elevates HIF1-α expression.

Why is Bay-805 highlighted as a therapeutic candidate?

Because USP21 inhibition by Bay-805 suppressed prostate cancer progression in the study, supporting its therapeutic potential.

Sep 23, 2026

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