Abstract
Glioblastoma (GBM), the most common and aggressive primary brain tumour, is associated with poor prognosis, primarily due to its stem-like subpopulation, glioblastoma stem cells (GSCs). The deubiquitinase (DUB) family has attracted an increasing amount of attention due to its roles in GSC biology and tumour aggressiveness. In this study, we focused on ubiquitin-specific peptidase 18 (USP18), a member of the DUB family whose role in GBM is poorly understood. Through integrated bioinformatics analyses and experimental investigations using patient-derived samples, cell models, and animal models, we elucidated the role of USP18 in enhancing GSC stemness and promoting malignant behaviours. Our findings revealed that USP18 expression is significantly elevated in GBM and is correlated with a poor prognosis. Mechanistically, USP18 interacts with SRY-box transcription factor 9 (SOX9), stabilising its protein levels by cleaving K48-linked polyubiquitin chains. Additionally, we identified YY1 as a transcriptional regulator of USP18, increasing its expression in GBM cells. These findings reveal that USP18 is a potential therapeutic target and highlight the novel YY1/USP18/SOX9 signalling axis implicated in GBM progression.
Overview
- The study focuses on the role of ubiquitin-specific peptidase 18 (USP18) in glioblastoma stem cells (GSCs) and its potential as a therapeutic target.
- The study uses a combination of bioinformatics analyses and experimental investigations to elucidate the role of USP18 in enhancing GSC stemness and promoting malignant behaviours.
- The study aims to overcome the poor prognosis associated with GBM by identifying key regulators and potential therapeutic targets, specifically USP18 and its signalling axis.
Comparative Analysis & Findings
- The study finds that USP18 expression is significantly elevated in GBM and is correlated with a poor prognosis, highlighting its potential as a therapeutic target.
- Mechanistically, USP18 interacts with SRY-box transcription factor 9 (SOX9), stabilising its protein levels by cleaving K48-linked polyubiquitin chains, which promotes GSC stemness and malignant behaviours.
- The study identifies YY1 as a transcriptional regulator of USP18, increasing its expression in GBM cells and contributing to the stabilisation of SOX9 protein levels, further propagating GSC stemness and malignant properties.
Implications and Future Directions
- The study provides a novel understanding of the USP18-SOX9-YY1 signalling axis and its role in promoting GSC stemness and malignant behaviours in GBM, highlighting potential therapeutic targets for treatment.
- Future research directions include exploring the therapeutic potential of targeting USP18 or its downstream effectors in pre-clinical models and clinical trials, as well as investigating the relationship between USP18 and other tumour suppressors or oncogenes.
- Understanding the molecular mechanisms underlying the association between USP18 expression and poor prognosis in GBM may lead to the development of novel diagnostic biomarkers and treatment strategies.