OTUD4 deubiquitination stabilizes EGFR and activates the PI3K/AKT pathway to promote the invasiveness of triple-negative breast cancer.

The deubiquitinating enzyme OTUD4 functions as an oncogene in various cancers, but its role in triple-negative breast cancer (TNBC) remains unclear. Through bioinformatics analysis and experimental validation, we demonstrate that OTUD4 is overexpressed in TNBC and correlates with poor prognosis. OTUD4 downregulation reduces TNBC invasiveness, highlighting its oncogenic role. Mechanistically, OTUD4 promotes TNBC progression by stabilizing EGFR expression and activating the PI3K/AKT pathway. This stabilization occurs through two mechanisms: direct interaction between OTUD4 (568-1114aa) and EGFR (958-1210aa) and OTUD4-mediated cleavage of K48-linked polyubiquitin chains. Additionally, OTUD4 is recruited by NRP1 to deubiquitinate and further stabilize EGFR. These findings enhance our understanding of EGFR signaling in TNBC and may inform novel therapeutic strategies.