ArticleCell death & disease2022
USP21 promotes self-renewal and tumorigenicity of mesenchymal glioblastoma stem cells by deubiquitinating and stabilizing FOXD1.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 31 citations in OpenAlex.
- USP5 in cancer: a therapeutic window into metabolism and drug resistance.Journal of translational medicine · 2026Review
- Integrating machine learning and spatial transcriptomics uncovers shared immunomodulatory deubiquitinases in MAFLD and HCC.Human genetics · 2026Article
- Dysregulation of post-translational modifications in glioma: advances in pathological mechanisms and clinical targeting strategies.Journal of translational medicine · 2026Review
- Defining treatment-resistant brain cancer: Genetic screening to identify oncogene-driven immunomodulation and therapy resistance.Cancer gene therapy · 2026Review
- USP21/YBX1/HIF1-α promotes the progression of prostate cancer.Journal of translational medicine · 2025Article
- Molecular Mechanisms of the Ubiquitin-Specific Proteases (USPs) Family in Biliary Tract Cancer and Targeted Intervention Strategies.Biomedicines · 2025Review
- Article
- Targeting USP21 to inhibit abdominal aortic aneurysm progression by suppressing the phenotypic transition of vascular smooth muscle cells.Cell reports. Medicine · 2025Article
- Review
- Phenotypic variations in glioma stem cells: regulatory mechanisms and implications for therapeutic strategies.Journal of translational medicine · 2025Review
- Identification and validation of a thirteen-gene signature based on ubiquitin related genes in cervical cancer.Discover oncology · 2025Article
- Role of antidiarrheal agents nifuroxazide in antitumor multi‑target anticancer, multi‑mechanism anticancer drug (Review).Oncology letters · 2025Review
- USP18 deubiquitinates and stabilizes SOX9 to promote the stemness and malignant progression of glioblastoma.Cell death discovery · 2025Article
- Sesquiterpene Lactones as Promising Anti-Glioblastoma Drug Candidates Exerting Complex Effects on Glioblastoma Cell Viability and Proneural-Mesenchymal Transition.Biomedicines · 2025Review
- Targeting ALG3/FOXD1/BNIP3 Axis Prevents Mitophagy and Gemcitabine Resistance of Nasopharyngeal Carcinoma.International journal of biological sciences · 2025Article
- Exploration of Diagnostic Deubiquitinating Enzymes in Endometriosis and Its Immune Infiltration.Biochemical genetics · 2024Article
- The ubiquitin-specific protease 21 is critical for cancer cell mitochondrial function and regulates proliferation and migration.The Journal of biological chemistry · 2024Article
- Neuropathological mRNA Expression Changes after Single Mild Traumatic Brain Injury in Pigs.Biomedicines · 2024Article
- UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.Cellular and molecular life sciences : CMLS · 2024Article
- Comprehensive understanding of glioblastoma molecular phenotypes: classification, characteristics, and transition.Cancer biology & medicine · 2024Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recent studies suggest that Forkhead box D1 (FOXD1) plays an indispensable role in maintaining the mesenchymal (MES) properties of glioblastoma (GBM) stem cells (GSCs). Thus, understanding the mechanisms that control FOXD1 protein expression is critical for guiding GBM treatment, particularly in patients with therapy-resistant MES subtypes. In this study, we identify the ubiquitin-specific peptidase 21 (USP21) as a critical FOXD1 deubiquitinase in MES GSCs. We find that USP21 directly interacts with and stabilizes FOXD1 by reverting its proteolytic ubiquitination. Silencing of USP21 enhances polyubiquitination of FOXD1, promotes its proteasomal degradation, and ultimately attenuates MES identity in GSCs, while these effects could be largely restored by reintroduction of FOXD1. Remarkably, we show that disulfiram, a repurposed drug that could block the enzymatic activities of USP21, suppresses GSC tumorigenicity in MES GSC-derived GBM xenograft model. Additionally, we demonstrate that USP21 is overexpressed and positively correlated with FOXD1 protein levels in GBM tissues, and its expression is inversely correlated with patient survival. Collectively, our work reveals that USP21 maintains MES identity by antagonizing FOXD1 ubiquitination and degradation, suggesting that USP21 is a potential therapeutic target for the MES subtype of GBM.
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