ArticleJournal of experimental & clinical cancer research : CR2024
STUB1-mediated K63-linked ubiquitination of UHRF1 promotes the progression of cholangiocarcinoma by maintaining DNA hypermethylation of PLA2G2A.
Article in Journal of experimental & clinical cancer research : CR, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Gastric cancer tertiary lymphoid structures in the muscularis propria are associated with therapy resistance and promote immunosuppression.Nature communications · 2026Article
- Article
- Transcriptomic profiling of epigenetic regulators and metabolic reprogramming in human cholangiocarcinoma.Frontiers in cell and developmental biology · 2026Article
- Article
- Multi-omics analysis unveils the role of cancer-associated fibroblasts in cutaneous squamous cell carcinoma.Cancer cell international · 2025Article
- USP20 competitively binds to STUB1 to enhance CTSL expression and promote epithelial-mesenchymal transition in head and neck squamous cell carcinoma.Clinical and translational medicine · 2025Article
- PDLIM4 drives gastric cancer malignant progression and cisplatin resistance by inhibiting HSP70 ubiquitination and degradation via competitive interaction with STUB1.Journal of nanobiotechnology · 2025Article
- Doublecortin-like kinase 1, regulated by STIP1 homology and U-box containing protein 1 or Sp1 transcription factor, affects the malignant behaviors and drug sensitivity in adriamycin-resistant breast cancer cells.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- LncRNA-CTD suppresses metastasis and immune evasion by modulating snail1 and MHC-I expression in colorectal cancer.Journal for immunotherapy of cancer · 2025Article
- Correction: STUB1-mediated K63-linked ubiquitination of UHRF1 promotes the progression of cholangiocarcinoma by maintaining DNA hypermethylation of PLA2G2A.Journal of experimental & clinical cancer research : CR · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
11 authors.
Funding
Abstract
backgroundCholangiocarcinoma (CCA) is a highly malignant tumor characterized by a lack of effective targeted therapeutic strategies. The protein UHRF1 plays a pivotal role in the preservation of DNA methylation and works synergistically with DNMT1. Posttranscriptional modifications (PTMs), such as ubiquitination, play indispensable roles in facilitating this process. Nevertheless, the specific PTMs that regulate UHRF1 in CCA remain unidentified.
methodsWe confirmed the interaction between STUB1 and UHRF1 through mass spectrometry analysis. Furthermore, we investigated the underlying mechanisms of the STUB1-UHRF1/DNMT1 axis via co-IP experiments, denaturing IP ubiquitination experiments, nuclear‒cytoplasmic separation and immunofluorescence experiments. The downstream PLA2G2A gene, regulated by the STUB1-UHRF1/DNMT1 axis, was identified via RNA-seq. The negative regulatory mechanism of PLA2G2A was explored via bisulfite sequencing PCR (BSP) experiments to assess changes in promoter methylation. The roles of PLA2G2A and STUB1 in the proliferation, invasion, and migration of CCA cells were assessed using the CCK-8 assay, colony formation assay, Transwell assay, wound healing assay and xenograft mouse model. We evaluated the effects of STUB1/UHRF1 on cholangiocarcinoma by utilizing a primary CCA mouse model.
resultsThis study revealed that STUB1 interacts with UHRF1, resulting in an increase in the K63-linked ubiquitination of UHRF1. Consequently, this facilitates the nuclear translocation of UHRF1 and enhances its binding affinity with DNMT1. The STUB1-UHRF1/DNMT1 axis led to increased DNA methylation of the PLA2G2A promoter, subsequently repressing its expression. Increased STUB1 expression in CCA was inversely correlated with tumor progression and overall survival. Conversely, PLA2G2A functions as a tumor suppressor in CCA by inhibiting cell proliferation, invasion and migration.
conclusionsThese findings suggest that the STUB1-mediated ubiquitination of UHRF1 plays a pivotal role in tumor progression by epigenetically silencing PLA2G2A, underscoring the potential of STUB1 as both a prognostic biomarker and therapeutic target for CCA.
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