TRIM47-mediated Ubiquitination of p53 Controls Proliferative Progression and Stress Adaptation in Glioblastoma

Glioblastoma (GBM) is a highly aggressive malignancy characterized by dysregulated cell proliferation and impaired stress-response control.Here, we identify the E3 ubiquitin ligase TRIM47 as a regulator of p53 proteostasis and proliferative signaling in GBM.Integrated bioinformatic analyses and immunohistochemistry revealed that TRIM47 is upregulated in GBM and associated with unfavorable survival.Functional assays demonstrated that TRIM47 depletion suppressed GBM cell proliferation and clonogenic growth, induced G1-phase arrest, and markedly inhibited intracranial tumor growth in vivo.Mechanistically, TRIM47 interacted with p53 through its RING-containing region and promoted K48-linked ubiquitination predominantly at lysine 319, leading to proteasome-dependent degradation of p53.Loss of TRIM47 results in stabilization of p53 protein, activation of p21, accumulation of DNA damage, and attenuation of cell-cycle progression.In GBM models exposed to temozolomide-induced genotoxic stress, TRIM47 expression was reduced whereas p53 signaling and DNA damage markers were elevated.Moreover, inhibition of PDK1 kinase activity impaired TRIM47-mediated p53 ubiquitination and enhanced p53-dependent stress responses.Collectively, these findings establish TRIM47 as a critical regulator of p53 proteostasis and cell-cycle progression in GBM, thereby maintaining proliferative fitness under genotoxic stress.