PSMD14 promotes breast cancer progression by reducing K63-linked ubiquitination on FOXM1 and activating the PI3K/AKT/mTOR pathway

The 26S Proteasome non-ATPase regulatory subunit 14 (PSMD14), a deubiquitinating enzyme (DUB), mediates progression in multiple malignancies. However, the functional significance of PSMD14 in breast Cancer remains incompletely characterized. This study aimed to investigate the oncogenic role and molecular mechanisms of PSMD14 in breast Cancer. PSMD14 expression patterns and prognostic value were examined through public databases. Cellular functional experiments were conducted to evaluate PSMD14's effect on tumor phenotypes. Mechanistic studies including co-immunoprecipitation (co-IP), immunofluorescence (IF), in vitro and in vivo deubiquitination assays were performed to delineate PSMD14-driven oncogenic mechanisms. Subcutaneous xenograft models established to validate the role of PSMD14 in vivo. Analysis revealed that elevated PSMD14 expression correlated with poor clinical prognosis in breast Cancer patients. PSMD14 promoted the proliferation, migration, and invasion of breast Cancer cells. Mechanistically, PSMD14 directly interacted with Forkhead box M1‌(FOXM1) and reduced the K63-linked ubiquitination on FOXM1. Furthermore, PSMD14 also activated the PI3K/Akt/mTOR pathway and enhanced cellular sensitivity to Cisplatin. Collectively, our findings demonstrate that PSMD14 promotes breast Cancer progression through dual mechanisms: deubiquitination of FOXM1 and activation of the PI3K/Akt/mTOR pathway. Thus, PSMD14 represents a potential therapeutic target for breast Cancer intervention.

Breast cancer; Cisplatin chemosensitivity; Deubiquitination; FOXM1; PI3K/AKT/mTOR pathway; PSMD14.