USP8-mediated CDH3 drives the malignant progression of lung adenocarcinoma by regulating ferroptosis

Ferroptosis has been found to be strongly associated with every stage of lung adenocarcinoma (LUAD), including initiation, proliferation, and progression. Moreover, reduced cadherin 3 (CDH3) is correlated with a better prognosis for LUAD and represses tumor cell proliferation and migration. However, whether CDH3 can be sufficient to mediate to malignant progression of lung cancer by modulating ferroptosis remains unclear.

GEPIA database was used to analyze CDH3 expression in LUAD patients, and the relationship between CDH3 and overall survival or ferroptosis-related protein glutathione peroxidase 4 (GPX4). CDH3 and deubiquitinating enzyme Ubiquitin-specific peptidase 8 (USP8) expressions were detected using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Cell viability, proliferation, death, migration, invasion, and angiogenesis were analyzed using Counting Kit (CCK-8), colony formation assay, flow cytometry, wound healing assay, Transwell assay, and tube formation assay. Fe^2 + level, malondialdehyde (MDA), lipid-ROS, and Glutathione (GSH) levels were determined using special kits. The stability of CDH3 was assessed by Cycloheximide (CHX) assay. After ubibrowser analysis, interaction between USP8 and CDH3 was verified using Co-immunoprecipitation (CoIP) assay. The role of USP8/CDH3 on LUAD tumor growth was examined using xenograft tumor model in vivo.

CDH3 and USP8 levels were increased in LUAD samples and cell lines. CDH3 silencing inhibited LUAD cell proliferation, migration, invasion, angiogenesis, and induced cell death and ferroptosis in vitro, as well as repressed tumor growth in vivo. Mechanistically, USP8 interacted with CDH3 and maintained its stabilization by removing ubiquitin.

USP8 contributed to LUAD development through deubiquitinating CDH3, providing a promising therapeutic target for LUAD treatment.