TRIM59 Drives Bladder Cancer Progression Through E3 Ligase‐Dependent K48‐Linked Degradation of PTRF

Abstract

ABSTRACT Tripartite motif‐containing 59 (TRIM59) is an E3 ubiquitin ligase implicated in multiple malignancies, but its role in bladder cancer (BLCA) remains incompletely understood. In this study, we identified TRIM59 as a clinically relevant oncogenic driver in BLCA through integrated transcriptomic, clinical, and functional analyses. TRIM59 was significantly upregulated in BLCA tissues and cell lines, and high TRIM59 expression was associated with advanced stage, higher grade, recurrence, and poor prognosis. Functionally, TRIM59 promoted BLCA proliferation, cell‐cycle progression, migration, invasion, and metastatic colonization in vitro and in vivo. Mechanistically, TRIM59 directly interacted with PTRF/Cavin‐1 and induced its RING domain‐dependent K48‐linked polyubiquitination and proteasomal degradation. Additional mutagenesis analyses identified K98, K122, K152, and K317 as major ubiquitination sites on PTRF. In contrast to the oncogenic role of TRIM59, PTRF was downregulated in BLCA and exhibited tumor‐suppressive properties. PTRF restoration attenuated TRIM59‐driven proliferation, invasion, and epithelial‐mesenchymal transition, whereas PTRF depletion partially rescued the inhibitory effects of TRIM59 silencing. Further analyses showed that PTRF restrains AKT phosphorylation and suppresses MYC transcriptional activity, thereby limiting c‐Myc‐driven proliferative signaling. Collectively, these findings define a previously unrecognized TRIM59–PTRF–AKT/c‐Myc axis that drives BLCA progression and highlight TRIM59 as a potential prognostic biomarker and therapeutic target.