Ramar Vanajothi, Sidhu Rajveer Singh, Pako Osei, Cisse Cheyenne R, Guo Alyssa A, Li Jason, Stapleton Kelcey, Guo Shanchun, Wang Guangdi, Liu Mingli
Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, 720 Westview Dr SW, Atlanta, GA, USA.
Spelman College, 350 Spelman Ln SW, Atlanta, GA, USA.
Cell Commun Signal. 2025 Jul 1;23(1):313. doi: 10.1186/s12964-025-02325-6.
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.
我们之前的研究表明，FOSL1通过STAT3和NF-κB信号传导等途径促进胶质母细胞瘤（GBM）的进展和干性。最近，我们发现FOSL1与核E3连接酶TRIM21存在物理相互作用。本研究调查了TRIM21在GBM中的作用，包括其与FOSL1的相互作用、对FOSL1反式激活的调节以及其通过泛素化介导的肿瘤抑制因子p27的降解。采用免疫沉淀试验评估TRIM21、FOSL1和p27之间的相互作用。通过过表达和siRNA介导的敲低来调控TRIM21的表达，以评估其对p27水平和泛素化的影响。分析TCGA和CGGA数据集，以探索TRIM21表达、胶质瘤亚型与患者生存之间的相关性。在调控TRIM21后，评估胶质瘤细胞增殖（MTT和集落形成）和侵袭（transwell试验）情况。对胶质瘤患者组织微阵列（TMA）进行免疫组织化学分析，评估TRIM21表达及其与FOSL1、IDH状态和胶质瘤分级的关联。通过AP-1结合位点分析核TRIM21在FOSL1启动子反式激活中的作用。TCGA和CGGA显示，TRIM21在GBM中高表达，尤其是在间充质亚型中，且与不良生存结果相关。功能试验表明，TRIM21增强胶质瘤细胞的增殖和侵袭。免疫组织化学证实胶质瘤中TRIM21水平升高，与FOSL1表达和胶质瘤分级呈正相关，与IDH1野生型状态呈负相关。从机制上讲，TRIM21与FOSL1和p27存在物理相互作用，通过AP-1结合位点反式激活FOSL1并促进p27泛素化和降解来驱动肿瘤发生。这些功能通过TRIM21的RING结构域介导p27降解及其PRYSPRY结构域介导FOSL1调节来实现。TRIM21通过降解肿瘤抑制因子p27并促进FOSL1反式激活，在GBM中发挥癌基因作用。这些发现突出了TRIM21作为GBM中一个有前景的治疗靶点。
