Glioblastoma (GBM) remains a lethal brain tumor with limited therapeutic efficacy from current standard care. The platelet-derived growth factor receptor alpha (PDGFRA) is a major oncogenic driver frequently amplified in gliomas. However, its high expression is paradoxically associated with improved prognosis in lower-grade gliomas, indicating a context-dependent role that is not fully understood. The regulatory mechanisms controlling PDGFRA protein stability represent a significant knowledge gap. In this study, we identify tripartite motif-containing 21 (TRIM21) as a previously uncharacterized E3 ubiquitin ligase for PDGFRA. We demonstrated that TRIM21 catalyzed K48-linked polyubiquitination specifically at lysine 606 of PDGFRA, directing PDGFRA for proteasomal degradation. Surprisingly, the oncogenic activity of TRIM21 was strictly dependent on PDGFRA expression. TRIM21 promoted malignant phenotypes specifically in PDGFRA-positive GBM cells, while exhibiting minimal or opposite effects in PDGFRA-negative cells. Mechanistically, TRIM21-mediated degradation of PDGFRA relieved a constitutive tumor-restraining function and simultaneously activated key downstream oncogenic pathways, including ERK, STAT3, and NF-κB, driving aggressive tumor progression. Clinically, elevated TRIM21 expression correlated with poor patient survival and confers resistance to both conventional radio-chemotherapy and the PDGFRA-targeted tyrosine kinase inhibitor imatinib in PDGFRA-high GBM. Our integrated analysis revealed an inverse correlation between TRIM21 and PDGFRA protein levels in patient specimens and highlighted TRIM21 upregulation as a feature of advanced disease. Collectively, these findings unveiled a crucial regulatory axis wherein TRIM21 switched PDGFRA from a context-dependent protective factor to an oncogenic driver and revealed TRIM21 as a prognostic biomarker and a therapeutic target for the PDGFRA-amplified subset of GBM.
Gai et al. (Wed,) studied this question.