Targeting ubiquitin-specific protease 14 reduces metastatic potential and metabolic activity in cervical cancer via direct modulation of monocarboxylate transporter-4

Sep 24, 2026

Ubiquitin-specific peptidase 14 (USP14) is investigated as a potential driver of tumorigenesis in cervical cancer, where its role in tumor metabolism remains unclear and HPV vaccination coverage is limited in low- and middle-income settings. Bioinformatic analyses and proteomics were integrated with validation in cervical cancer cell lines and non-transformed controls. USP14 was inhibited by knockdown or IU1, followed by assays for viability, metastasis, and invasion, and by proteomics to identify USP14 partners focused on MCT4.

LanguageEnglish

CategoryHealthcare

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Pages24

Reading Time1 h 0 min

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Abstract

Background

Methods

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Introduction

Chauhan et al. Journal of Translational Medicine (2026) 24:33 [https://doi.org/10.1186/s12967-025-07442-x](https://doi.org/10.1186/s12967-025-07442-x) Journal of Translational Medicine RESEARCH Open Access Targeting ubiquitin-specific protease 14 reduces metastatic potential and metabolic activity in cervical cancer via direct modulation of monocarboxylate transporter-4 Ravi Chauhan 1, Gunjan Dagar 1, Lakshay Mal hotra2, Ashna Gupta 1, Anju Surendranath3, Harshul Kapoor 1, HemantYadav4, Rajat Ujjainiya5,6, Suraja Kumar Das 1, Sameer Mirza7, Mukesh Tanwar8, Pranay Tanwar9, Abdul S. Ethayathulla 10, Archana Singh 11, Muzafar A. Macha 12, Shahab Uddin 13,14, Ammira S. Al-Shabeeb Akil3, Sandeep Mathur 15, Tej K. Pandita 16, Ajaz A. Bhat3* and Mayank Singh 1* Abstract Background Cervical cancer (CC) remains a major health burden in low-and middle-income countries, where HPV vaccination coverage is suboptimal. Ubiquitin-specific peptidase 14 (USP14), a proteasome-associated deubiquitinase, has emerged as a potential driver of tumorigenesis, but its role in CC and impact on tumor metabolism remain poorly defined. Methods In-sil ico analysis of RNA and proteomics data from publicly available datasets was performed to assess the expression and prognostic value of USP14 . Expression was validated in CC cell lines (HeLa, SiHa, CaSki) in comparison to non-transformed MCF10A cells. Functional studies involved USP14 knockdown (siRNA) or inhibition (IU1), followed by various cell viability, metastasis and invasion assays. Comparative proteomics was employed to identify USP14 interacting partners, with a particular focus on monocarboxylate transporter 4 (MCT4) . USP14-MCT4 interactions were confirmed by co-immunoprecipitation, ubiquitination assays, and molecular dynamics simulations. Immunohistochemistry was performed on retrospective cervical squamous cell carcinoma tissues to correlate USP14 and MCT4 expression. Results High USP14 expression correlated with poor overall survival in CC patients and was elevated in CC cell lines. Genetic or pharmacological inhibition of USP14 significantly reduced CC cell proliferation, metastasis, and invasion. Proteomic profiling identified MCT4, a key lactate transporter in tumor metabolism, as a novel USP14 interactor. USP14 knockdown decreased MCT4 protein levels and stability, suggesting deubiquitination-dependent regulation. Immunoprecipitation confirmed direct binding between USP14 and MCT4, and molecular dynamics simulations revealed distinct binding interfaces. In patient tissues, USP14 and MCT4 expression were positively correlated. *Correspondence: Ajaz A. Bhat[abhat@sidra.org](abhat@sidra.org)[ ](abhat@sidra.org)Mayank Singh [mayank.osu@gmail.com](mayank.osu@gmail.com) 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/. Chauhan et al. Journal of Translational Medicine (2026) 24:33 Page 2 o

FAQs

What was the main goal of the study on USP14 and cervical cancer?

To determine whether USP14 influences cervical cancer progression and tumor metabolism, with emphasis on identifying metabolic partners such as MCT4.

How was USP14 inhibition performed in the experiments?

USP14 activity was reduced using siRNA knockdown or pharmacological inhibition with IU1, followed by functional assays for cell viability, metastasis, and invasion.

What role did MCT4 play in the USP14 mechanism?

Proteomic profiling identified MCT4 as a USP14 interactor; USP14 knockdown lowered MCT4 protein levels and stability, and binding was supported by immunoprecipitation and molecular dynamics.

Sep 24, 2026

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