ArticleCellular and molecular life sciences : CMLS2024
UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.
Article in Cellular and molecular life sciences : CMLS, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- UCHL3 Promotes Triple-Negative Breast Cancer Metastatic Potential Through Enhancing Cell Migration and Invasion.Applied biochemistry and biotechnology · 2026Article
- Deubiquitinating Enzymes as Therapeutic Candidates in Hepatocellular Carcinoma and Other Liver Disease.International journal of molecular sciences · 2026Review
- Molecular insights into DNA damage response plasticity in glioma stem cells.Communications biology · 2026Review
- Deciphering the glioblastoma microenvironmental landscape with multi-modal radiogenomics to guide prognosis and personalized therapy.Journal of translational medicine · 2026Article
- The Role of Chaf1b in Maintaining Glioma Stem Cell Stemness and Regulating Microglial Polarization.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Decoding the ubiquitin network: molecular mechanisms and therapeutic vulnerabilities for precision radio-sensitization in cancer.Molecular cancer · 2025Review
- Phenotypic variations in glioma stem cells: regulatory mechanisms and implications for therapeutic strategies.Journal of translational medicine · 2025Review
- A novel neutrophil extracellular trap-related gene signature for predicting glioblastoma prognosis.Scientific reports · 2025Article
- UCHL3 regulates snail stability and promotes epithelial-mesenchymal transition in ovarian cancer.Cytotechnology · 2025Article
- Review
- RNA Sequencing Identifies Novel Signaling Pathways and Potential Drug Target Genes Induced by FOSL1 in Glioma Progression and Stemness.Biologics : targets & therapy · 2025Article
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15 authors.
Funding
Abstract
backgroundThe high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive.
methodExpression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS.
resultWe determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model.
conclusionThese findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.
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