PFKP deubiquitination and stabilization - by USP5 activate aerobic glycolysis to promote triple-negative breast cancer progression

Sep 22, 2026

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Triple-negative breast cancer (TNBC) remains difficult to treat and lacks definite therapeutic targets. Aerobic glycolysis drives metabolic reprogramming in cancer progression, and PFKP is a rate-limiting glycolytic enzyme that is overexpressed across malignancies. This study investigates how PFKP posttranslational deubiquitination and stabilization contribute to TNBC progression, using proteomic data, cellular assays, and in vivo xenograft experiments, with focus on the USP5-PFKP regulatory axis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Background

Triple-negative breast cancer and therapeutic need

Aerobic glycolysis and PFKP as a glycolytic regulator

Methods

Expression assessment and functional studies

USP5–PFKP pathway verification

Results

PFKP expression, prognosis association, and functional inhibition

USP5-mediated deubiquitination and stabilization

Correlation between USP5 and PFKP in TNBC

Conclusions

USP5–PFKP axis as a therapeutic rationale

Peng et al. Breast Cancer Research (2024) 26:10 [https://doi.org/10.1186/s13058-024-01767-z](https://doi.org/10.1186/s13058-024-01767-z) Breast Cancer Research RESEARCH Open Access PFKP deubiquitination and stabilization by USP5 activate aerobic glycolysis to promote triple-negative breast cancer progression Zi‑Mei Peng 1, Xiao‑Jian Han2, Tao Wang2, Jian‑Jun Li3, Chun‑Xi Yang1, Fang‑Fang Tou4* and Zhen Zhang1* Abstract Background Triple‑negative breast cancer (TNBC) remains the most challenging subtype of breast cancer and lacks definite treatment targets. Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to cancer progression. PFKP is a rate‑limiting enzyme involved in aerobic glycolysis, which is overexpressed in various types of cancers. However, the underlying mechanisms and roles of the posttranslational modification of PFKP inTNBC remain unknown. Methods To explore whether PFKP protein has a potential role in the progression ofTNBC, protein levels of PFKPinTNBC and normal breast tissues were examined by CPTAC database analysis, immunohistochemistry staining (IHC), and western blotting assay. Further CCK‑8 assay, colony formation assay, EDU incorporation assay, and tumor xeno‑ graft experiments were used to detect the effect of PFKP onTNBC progression. To clarify the role of the USP5‑PFKP pathway inTNBC progression, ubiquitin assay, co‑immunoprecipitation (Co‑IP), mass spectrometry‑based protein identification, western blotting assay, immunofluorescence microscopy, in vitro binding assay, and glycolysis assay were conducted. Results Herein, we showed that PFKP protein was highly expressed inTNBC, which was associated with TNBC progression and poor prognosis of patients. In addition, we demonstrated that PFKP depletion significantly inhibited the TNBC progression in vitro and in vivo. Importantly, we identified that PFKP was a bona fide target of deubiquit‑ inase USP5, and the USP5‑mediated deubiquitination and stabilization of PFKP were essential for cancer cell aerobic glycolysis and TNBC progression. Moreover, we found a strong positive correlation between the expression of USP5 and PFKP inTNBC samples. Notably, the high expression of USP5 and PFKP was significantly correlated with poor clini‑ cal outcomes. Conclusions Our study established the USP5‑PFKP axis as an important regulatory mechanism ofTNBC progression and provided a rationale for future therapeutic interventions in the treatment ofTNBC. Keywords TNBC, USP5, PFKP, Aerobic glycolysis, Cancer progression *Correspondence: Fang‑Fang Tou [toufangfang@163.com](toufangfang@163.com)[ ](toufangfang@163.com)Zhen Zhang [nkzhenzhang@163.com](nkzhenzhang@163.com) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. 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://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[. The Creative Commons Public Domain Dedication waiver (](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[http://creativecom](http://creativecom)‑ [mons.org/publicdomain/zero/1.0

FAQs

What is the key question the study addresses about TNBC?

The study examines whether PFKP has a functional role in TNBC progression and what underlying mechanism—specifically posttranslational modification—drives that role.

How was PFKP’s role in TNBC progression tested?

PNK-related protein levels in TNBC and normal tissues were assessed, and PFKP effects were evaluated using cell-based assays (CCK-8, colony formation, EDU incorporation) and tumor xenograft experiments.

What pathway connects USP5 to PFKP in this research?

USP5 was identified as a deubiquitinase targeting PFKP, and USP5-mediated deubiquitination and stabilization of PFKP were shown to be essential for aerobic glycolysis and TNBC progression.

What clinical relevance does the study report?

USP5 and PFKP expression levels in TNBC samples showed a positive correlation and were significantly associated with poor clinical outcomes.

Sep 22, 2026

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