SETD5 in glioma cells conferred TRAIL resistance induction

Glioblastoma (GBM) is the most aggressive and lethal form of primary brain tumor, often characterized by resistance to conventional therapies and a poor clinical prognosis. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) selectively induces apoptosis in cancer cells; however, TRAIL resistance remains a significant obstacle in GBM treatment. SETD5, a histone methyl transferase with emerging roles in chromatin remodeling and gene regulation, has been implicated in neurodevelopmental disorders and cancer, but remains poorly characterized in glioma biology. This study investigates the role of SETD5 in modulating TRAIL resistance and explores its potential as a therapeutic target in GBM. Publicly available datasets (TCGA, GTEx, GEPIA2, UALCAN, Gliovis, and GSCA) were used to assess SETD5 expression, mutation, and promoter methylation in GBM. Associations with clinical parameters, molecular subtypes, immune infiltration, and functional states were analyzed using tools like cBioPortal, CancerSEA, MEXPRESS, and STRING. siRNA-mediated knockdown of SETD5 was performed in U87 and LN229 GBM cell lines, followed by TRAIL treatment. Western blotting assessed changes in apoptotic and survival pathways, while wound healing assays evaluated cell migration. Expression of deubiquitinases (USP5, USP8, and USP10) was also measured. SETD5 was significantly upregulated in GBM compared to normal brain tissues across multiple databases and was especially elevated in the Mesenchymal and Classical subtypes. CNV analyses revealed alterations in SETD5 that correlated with immunosuppressive cell infiltration. SETD5 expression was positively correlated with survival pathways and negatively correlated with cytotoxic immune infiltration. TRAIL treatment induced SETD5 expression in a dose-dependent manner. Knockdown of SETD5 enhanced TRAIL-mediated apoptosis, reduced expression of survival markers (p-AKT, P-ERK, NF-κB), and increased pro-apoptotic proteins (Cytochrome c, SMAC). SETD5 depletion also downregulated USP5, USP8, and USP10, suggesting its role in stabilizing oncogenic proteins via deubiquitination. SETD5 plays a critical role in promoting TRAIL resistance and GBM survival by regulating apoptotic pathways, immune evasion, and deubiquitinase expression. Moreover knockdown of SETD along with TRAIL treatment leads to down regulation NFκB which a major promoter for cell survival. Its inhibition sensitizes glioma cells to TRAIL-induced apoptosis, identifying SETD5 as a potential therapeutic target. Targeting SETD5 could represent a novel strategy to overcome TRAIL resistance and enhance the efficacy of GBM therapies.