Skip to content
DraconiticResearch
Search Sources API
206,690 studies31 sourcesUpdated 23 min ago
Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

The Deubiquitinating Enzyme UCHL1 Promotes Radiotherapy Resistance in Glioma by Stabilizing Keratin 18

  • Hanlu Wang1,2
  • Rujuan Zheng1,2
  • Qian Liu3
  • Xinyuan Ding4
  • Ying Zhao1
  • Jianyu Xu4
  • Ruze Tang5
  • Lulu Chen5
  • Xi Chen1,2
  • Hui Shi1,2
  • Huiling Zhang2
  • Wenjuan Wang1,2
5 affiliations
  1. 1Department of Pharmacy, Children’s Hospital of Soochow University, Suzhou 215025, China
  2. 2College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
  3. 3Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou 215001, China
  4. 4Department of Pharmacy, Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou 215001, China
  5. 5Department of Surgical Oncology, Children’s Hospital of Soochow University, Suzhou 215025, China
Open at sourceDOICite

Abstract

Maintaining stemness in glioma stem cells (GSCs), coupled with robust DNA damage repair capacity, is a key determinant of radioresistance in glioma. Although the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1 (UCHL1) has been implicated in regulating tumor cell functions and facilitating malignant progression, its specific role in sustaining GSC stemness and in promoting radioresistance remains poorly understood. In this study, we combined secondary analyses of public datasets with in–house experimental investigations. Specifically, we first analyzed UCHL1 expression and its prognostic significance in glioma using the GEO2R, GEPIA2, and CGGA databases. Radiosensitivity, DNA repair capability, and GSC stemness were evaluated using clonogenic survival, comet, sphere formation, extreme limiting dilution assay, and Western blot analyses. To identify UCHL1–interacting proteins, co-immunoprecipitation coupled with mass spectrometry was performed, followed by deubiquitination and rescue experiments to validate its substrates and functional dependence. Our results revealed that UCHL1 was markedly overexpressed in radioresistant glioblastoma cells and glioma tissues, and its expression levels positively correlated with poor prognosis in patients with glioma. UCHL1 knockdown attenuated the sphere-forming capacity and self–renewal frequency of GSCs and impaired the cellular response to DNA damage following irradiation, thereby attenuating the radioresistant phenotype. Mechanistically, UCHL1 stabilizes keratin 18 (KRT18) protein via deubiquitination. The effects of UCHL1 on radioresistance and stemness properties were largely diminished upon KRT18 knockdown, accompanied by reduced expression of the stemness marker SOX2. Furthermore, KRT18 knockdown attenuated the radioresistant phenotype induced by UCHL1 overexpression. Collectively, these findings suggest a mechanistic axis through which UCHL1 may regulate GSC stemness and radioresistance and identify UCHL1 as a candidate therapeutic target for reversing therapeutic resistance in glioma, warranting further validation.

Related

  1. Deubiquitinase USP5 suppresses ferroptosis in lung adenocarcinoma by deubiquitinating and stabilizing GPX3.
    Xin Fan, Yubiao Lin, Zhigao Zhen +6
    Journal of cell communication and signalingPeer-reviewedCC BYFull textMolecular biology & gene regulationEurope PMC
  2. USP11 Drives Cerebral Ischemia–Reperfusion Injury Via Promoting Ferroptosis by Deubiquitinating and Stabilizing ASK1
    Sha Hu, KunPeng Wang, Mingcheng He +6
    Journal of the American Heart AssociationPeer-reviewedCC BY-NC-NDMolecular biology & gene regulationCrossref
  3. Monocyte-Mimetic Nanoparticle Delivery of Verteporfin Promotes Plaque-Stabilizing Remodeling in Atherosclerosis
    T.-Y. Wang, A. Zehnder, S.-P. Wu +3
    bioRxivPreprintAll rights reservedFull textMolecular biology & gene regulationbioRxiv
  4. Mechanosignaling Promotes Macrophage Apoptosis Resistance in Pulmonary Fibrosis via Metabolic Reprogramming
    C. He, C. Coarfa, N. Garcia +15
    bioRxivPreprintAll rights reservedFull textMolecular biology & gene regulationbioRxiv
  5. Activity-based proteomics discovery of deubiquitinating enzyme inhibitors with immunomodulatory activity
    Hannah B. L. Jones, Simeon D. Draganov, Sofia Schönbauer Huamán +27
    npj Drug DiscoveryPeer-reviewedCC BY 4.0Full textMolecular biology & gene regulationPMC

Cite

BibTeXRIS
BibTeX
@article{wang2026deubiquitinating,
  title = {{The Deubiquitinating Enzyme UCHL1 Promotes Radiotherapy Resistance in Glioma by Stabilizing Keratin 18}},
  author = {Hanlu Wang and Rujuan Zheng and Qian Liu and Xinyuan Ding and Ying Zhao and Jianyu Xu and Ruze Tang and Lulu Chen and Xi Chen and Hui Shi and Huiling Zhang and Wenjuan Wang},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = nov,
  doi = {10.3390/ijms27219875},
  url = {https://www.mdpi.com/1422-0067/27/21/9875},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - The Deubiquitinating Enzyme UCHL1 Promotes Radiotherapy Resistance in Glioma by Stabilizing Keratin 18
AU  - Hanlu Wang
AU  - Rujuan Zheng
AU  - Qian Liu
AU  - Xinyuan Ding
AU  - Ying Zhao
AU  - Jianyu Xu
AU  - Ruze Tang
AU  - Lulu Chen
AU  - Xi Chen
AU  - Hui Shi
AU  - Huiling Zhang
AU  - Wenjuan Wang
PY  - 2026
DA  - 2026/11/04
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219875
UR  - https://www.mdpi.com/1422-0067/27/21/9875
AB  - Maintaining stemness in glioma stem cells (GSCs), coupled with robust DNA damage repair capacity, is a key determinant of radioresistance in glioma. Although the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1 (UCHL1) has been implicated in regulating tumor cell functions and facilitating malignant progression, its specific role in sustaining GSC stemness and in promoting radioresistance remains poorly understood. In this study, we combined secondary analyses of public datasets with in–house experimental investigations. Specifically, we first analyzed UCHL1 expression and its prognostic significance in glioma using the GEO2R, GEPIA2, and CGGA databases. Radiosensitivity, DNA repair capability, and GSC stemness were evaluated using clonogenic survival, comet, sphere formation, extreme limiting dilution assay, and Western blot analyses. To identify UCHL1–interacting proteins, co-immunoprecipitation coupled with mass spectrometry was performed, followed by deubiquitination and rescue experiments to validate its substrates and functional dependence. Our results revealed that UCHL1 was markedly overexpressed in radioresistant glioblastoma cells and glioma tissues, and its expression levels positively correlated with poor prognosis in patients with glioma. UCHL1 knockdown attenuated the sphere-forming capacity and self–renewal frequency of GSCs and impaired the cellular response to DNA damage following irradiation, thereby attenuating the radioresistant phenotype. Mechanistically, UCHL1 stabilizes keratin 18 (KRT18) protein via deubiquitination. The effects of UCHL1 on radioresistance and stemness properties were largely diminished upon KRT18 knockdown, accompanied by reduced expression of the stemness marker SOX2. Furthermore, KRT18 knockdown attenuated the radioresistant phenotype induced by UCHL1 overexpression. Collectively, these findings suggest a mechanistic axis through which UCHL1 may regulate GSC stemness and radioresistance and identify UCHL1 as a candidate therapeutic target for reversing therapeutic resistance in glioma, warranting further validation.
SN  - 1422-0067
ER  -