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Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review)

  • Authors:
    • Chang-Zhu Pei
    • Xiao-Xing Song
    • Hao Xu
    • Kwang-Hyun Baek
  • View Affiliations / Copyright

    Affiliations: Department of Gynecology, Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu 222000, P.R. China, Department of Biomedical Science, CHA University, Seongnam, Gyeonggi 13488, Republic of Korea
    Copyright: © Pei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 79
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    Published online on: May 14, 2026
       https://doi.org/10.3892/ijo.2026.5892
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Abstract

Cervical cancer (CC) remains a major global gynecological malignancy, with a rising incidence among younger women in specific regions. Human papillomavirus (HPV) screening and cytological examination have markedly reduced the disease burden; nonetheless, tumor progression, therapeutic resistance and recurrence continue to pose major clinical challenges. Thus, elucidating the molecular mechanisms underlying the progression of CC is crucial. Deubiquitinating enzymes (DUBs) regulate ubiquitin‑dependent protein turnover and signaling, emerging as vital modulators of cell cycle progression, DNA damage response, apoptosis, immune regulation and HPV‑associated carcinogenesis. Notably, DUBs facilitate CC progression by stabilizing oncogenic proteins, regulating tumor suppressors and modulating major signaling pathways. In addition, several DUBs are closely associated with radiosensitivity, chemoresistance and potential targeted therapeutic strategies. The present review summarizes the molecular mechanisms and therapeutic implications of DUBs in CC, while discussing their translational value for future clinical applications.
View Figures

Figure 1

Classification of human DUBs. Human
DUBs are classified into cysteine protease or metallopeptidase
families based on their sequence and structural features. The
largest family comprises 58 USPs, followed by 19 OTUs and 9 JAMM
metallopeptidases. Additional cysteine protease families include 5
MINDY proteins, 4 UCHs, 4 MCPIP-related proteins, 4 MJDs, 2 PPPDEs
and ZUP1. Individual family members are listed within each colored
box. Proteins marked with an asterisk are predicted to lack
catalytic activity based on their amino-acid sequence analysis or
structural evidence. DUB, deubiquitinating enzyme; JAMM
metallopeptidase, JAMM/MPN domain-associated metallopeptidase;
MCPIP, monocyte chemotactic protein-induced protein; MINDY,
motif-interacting with ubiquitin-containing novel DUB; MJD,
Machado-Joseph domain-containing protease; OTU, ovarian
tumor-related protease; PPPDE, permuted papain fold peptidase of
dsRNA viruses and eukaryotes; UCH, ubiquitin C-terminal hydrolase;
USP, ubiquitin-specific peptidase; ZUP1, zinc finger-containing
ubiquitin peptidase 1.

Figure 2

Regulatory network of USPs in tumor
progression and therapy resistance. Schematic diagram illustrating
the roles of multiple USPs and their downstream targets in
regulating malignant phenotypes in CC. USP3, USP7, USP8, USP11,
USP15, USP17, USP18, USP19, USP21, USP26, USP39, USP45, USP53 and
CYLD modulate diverse oncogenic or tumor-suppressive pathways
through substrates or signaling mediators including Cdc25A, MTDH,
EZH2, TIMP2, NF-κB, PD-L1, Fas, TRAIL, TNF-α, HPV E6/E7, pRb,
Bcl-2, Cdc2, Ras, HDAC, MEK/ERK, PI3K/JNK, MDM2, p53, KLF6, Myc,
CDK1/2, DDB2, Bax, Aurora B, SIRT7, FOXM1, and YAP1. These
signaling events converge on key cancer-associated processes,
including proliferation, apoptosis, immune escape, invasion,
migration, stemness, angiogenesis, drug resistance, radioresistance
and cell cycle regulation. The influence of non-coding RNAs and
microenvironmental cues, such as hypoxia/miRNA-100 and miRNA-501,
as well as small molecule modulators, including α-mangostin and
IU1, on USP-centered signaling networks are also highlighted.
Arrows indicate activation or positive regulation, whereas
blunt-ended lines indicate inhibition or negative regulation.
Overall, the diagram emphasizes the central role of USP-mediated
deubiquitination in coordinating tumor progression, cellular
adaptation and therapeutic response in CC. CC, cervical cancer;
Cdc, cell division cycle; DDB2, DNA damage-binding protein 2; DUB,
deubiquitinating enzyme; FLIPL, FLICE-like inhibitory protein;
HDAC, histone deacetylase; HPV, human papillomavirus; KLF6,
Krüppel-like factor 6; MDM2, murine double minute protein 2; miRNA,
microRNA; MTDH, metadherin; SDS3, HDAC-dependent Sin3A co-repressor
complex; USP, ubiquitin-specific protease.

Figure 3

Regulatory roles of DUBs and
associated factors in tumor progression. Schematic diagram
illustrating how multiple DUBs and related regulatory proteins
contribute to malignant phenotypes in CC through distinct
downstream signaling pathways. Members of the UCH family, including
UCHL1, UCHL3 and UCHL5; as well as BAP1, CSN5, CSN6, BRCC3, EIF3F,
OTUD1 and OTUB2, modulate the stability or activity of key
effectors involved in tumor progression. Their downstream targets
include PROX1, NRF2, β-catenin, ENO3, E6AP, p53, E-cadherin,
vimentin, MMP-2/-9, Snail-1/-2, GSK-3β, Elk-1/Egr-1, p53/p21/Bax,
MCL1, OUN-36, AKT/mTOR, FOXM1 and RBM15. Through these regulatory
interactions, DUBs influence major cancer-related processes,
including proliferation, apoptosis, invasion, migration, metastasis
and drug resistance. Upstream regulation by miRNA-31 targeting BAP1
is also shown, and pathway crosstalk involving AKT/ERK and AKT/mTOR
signaling is highlighted. Arrows indicate activation or positive
regulation, whereas lines indicate inhibition or negative
regulation. Overall, the diagram emphasizes the central role of
deubiquitination-dependent signaling in coordinating tumor growth,
dissemination and therapeutic response in CC. BAP1,
BRCA1-associated protein-1; CC, cervical cancer; DUB,
deubiquitinating enzyme; EMT, epithelial-mesenchymal transition;
ENO3, enolase 3; HK2, hexokinase 2; LDHA, lactate dehydrogenase A;
miRNA, microRNA; NRF2, nuclear factor erythroid 2-related factor 2;
OTU, ovarian tumor-related protease; PKM2, pyruvate kinase M2;
PROX1, prospero homeobox 1; UCH, ubiquitin C-terminal hydrolase;
USP, ubiquitin-specific protease.
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Copy and paste a formatted citation
Spandidos Publications style
Pei C, Song X, Xu H and Baek K: Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review). Int J Oncol 69: 79, 2026.
APA
Pei, C., Song, X., Xu, H., & Baek, K. (2026). Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review). International Journal of Oncology, 69, 79. https://doi.org/10.3892/ijo.2026.5892
MLA
Pei, C., Song, X., Xu, H., Baek, K."Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review)". International Journal of Oncology 69.1 (2026): 79.
Chicago
Pei, C., Song, X., Xu, H., Baek, K."Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review)". International Journal of Oncology 69, no. 1 (2026): 79. https://doi.org/10.3892/ijo.2026.5892
Copy and paste a formatted citation
x
Spandidos Publications style
Pei C, Song X, Xu H and Baek K: Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review). Int J Oncol 69: 79, 2026.
APA
Pei, C., Song, X., Xu, H., & Baek, K. (2026). Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review). International Journal of Oncology, 69, 79. https://doi.org/10.3892/ijo.2026.5892
MLA
Pei, C., Song, X., Xu, H., Baek, K."Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review)". International Journal of Oncology 69.1 (2026): 79.
Chicago
Pei, C., Song, X., Xu, H., Baek, K."Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review)". International Journal of Oncology 69, no. 1 (2026): 79. https://doi.org/10.3892/ijo.2026.5892
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