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TRIM21 functions as an oncogene in glioblastoma by transactivating FOSL1 and promoting the ubiquitination of p27
Vanajothi Ramar1, Rajveer Singh Sidhu1, Osei Pako1
1Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, 720 Westview Dr SW, Atlanta, GA, USA.
Abstract:
Our previous studies demonstrated that FOSL1 promotes glioblastoma (GBM) progression and stemness through pathways such as STAT3 and NF-κB signaling. Recently, we identified that FOSL1 physically interacts with the nuclear E3 ligase TRIM21. This study investigates the role of TRIM21 in GBM, including its interaction with FOSL1, its regulation of FOSL1 transactivation, and its ubiquitination-mediated degradation of tumor suppressor p27. Immunoprecipitation assays were used to evaluate the interactions between TRIM21, FOSL1, and p27. TRIM21 expression was manipulated through overexpression and siRNA-mediated knockdown to assess its effects on p27 levels and ubiquitination. TCGA and CGGA datasets were analyzed to explore correlations between TRIM21 expression, glioma subtypes, and patient survival. Glioma cell proliferation (MTT and colony formation) and invasion (transwell assays) were evaluated following TRIM21 manipulation. Immunohistochemistry on glioma patient tissue microarray (TMA) assessed TRIM21 expression and its association with FOSL1, IDH status, and glioma grade. The role of nuclear TRIM21 in FOSL1 promoter transactivation was analyzed via AP-1 binding sites. TCGA and CGGA revealed that TRIM21 is highly expressed in GBM, particularly in the mesenchymal subtypes, and correlates with poor survival outcomes. Functional assays demonstrated that TRIM21 enhances glioma cell proliferation and invasion. Immunohistochemistry confirmed elevated TRIM21 levels in gliomas, positively correlating with FOSL1 expression and glioma grade, and inversely correlating with IDH1 wild-type status. Mechanistically, TRIM21 physically interacts with FOSL1 and p27, driving tumorigenesis by transactivating FOSL1 via AP-1 binding sites and promoting p27 ubiquitination and degradation. These functions are mediated through TRIM21's RING domain for p27 degradation and its PRYSPRY domain for FOSL1 regulation. TRIM21 functions as an oncogene in GBM by degrading the tumor suppressor p27 and promoting FOSL1 transactivation. These findings highlight TRIM21 as a promising therapeutic target in GBM.
Insights
The nuclear E3 ligase TRIM21 promotes glioblastoma by degrading tumor suppressor p27 and enhancing FOSL1 activity. TRIM21 is a potential therapeutic target for glioblastoma (GBM).
Area of Science:
- Molecular Oncology
- Cancer Biology
- Neuro-oncology
Background:
- FOSL1 is known to drive glioblastoma (GBM) progression and stemness via STAT3 and NF-κB signaling.
- FOSL1 was recently found to interact with the nuclear E3 ligase TRIM21, suggesting a role for TRIM21 in GBM pathogenesis.
Purpose of the Study:
- To investigate the role of TRIM21 in glioblastoma (GBM).
- To elucidate the interaction between TRIM21 and FOSL1, and TRIM21's regulation of FOSL1 transactivation.
- To determine TRIM21's role in the ubiquitination and degradation of the tumor suppressor p27.
Main Methods:
- Immunoprecipitation assays to assess interactions between TRIM21, FOSL1, and p27.
- Manipulation of TRIM21 expression (overexpression and siRNA knockdown) to study effects on p27.
- Analysis of TCGA and CGGA datasets for TRIM21 expression, glioma subtypes, and survival correlations.
- Functional assays (MTT, colony formation, transwell) to evaluate proliferation and invasion.
- Immunohistochemistry on glioma tissue microarrays (TMA) to assess TRIM21 expression and associations.
- Reporter assays to analyze TRIM21's role in FOSL1 promoter transactivation.
Main Results:
- TCGA and CGGA data show high TRIM21 expression in GBM, especially mesenchymal subtypes, correlating with poor survival.
- TRIM21 enhances glioma cell proliferation and invasion.
- TRIM21 physically interacts with FOSL1 and p27, promoting FOSL1 transactivation via AP-1 sites and inducing p27 ubiquitination and degradation.
- TRIM21 expression correlates positively with FOSL1 and glioma grade, and inversely with IDH1 wild-type status.
Conclusions:
- TRIM21 functions as an oncogene in GBM by degrading the tumor suppressor p27 and promoting FOSL1 transactivation.
- TRIM21's oncogenic functions are mediated by its RING domain (for p27 degradation) and PRYSPRY domain (for FOSL1 regulation).
- TRIM21 represents a promising therapeutic target for glioblastoma.
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