PSMD12 Overexpression Promotes Lung Adenocarcinoma Progression via Ubiquitin–Proteasome Pathway Dysregulation

Lung adenocarcinoma (LUAD) is one of the most common cancers and a leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutic strategies. Proteasome 26S Subunit, Non-ATPase 12 (PSMD12), a component of the proteasomal 19S regulatory particle, is associated with tumorigenesis; however, its role in LUAD remains poorly understood. Integrative bioinformatic analysis of The Cancer Genome Atlas (TCGA) and other publicly available LUAD datasets identified PSMD12 as a candidate driver gene on chromosome 17q, a region frequently amplified in LUAD. Clinicopathological and prognostic analyses revealed that PSMD12 was significantly upregulated in tumor tissues because of DNA copy number gain. High PSMD12 expression was associated with poor prognosis and advanced pathological stages. Gene set enrichment analysis of TCGA LUAD dataset demonstrated that samples with high PSMD12 expression were enriched for cell cycle-related pathways. Using CRISPR-Cas9-mediated PSMD12 knockout and lentivirus-mediated overexpression models, we demonstrated that PSMD12 promoted tumor cell proliferation by accelerating the G2/M cell cycle transition in vitro, and xenograft experiments confirmed its tumor-promoting effect in vivo. Mechanistically, PSMD12 overexpression reduced the ubiquitination of CDK1, a key regulator of mitotic entry. Cycloheximide chase and MG132 assays confirmed that PSMD12 stabilized CDK1 by inhibiting proteasome-mediated degradation. In conclusion, we identified PSMD12 as a novel driver gene and prognostic biomarker of LUAD. PSMD12 promoted LUAD progression by modulating CDK1 ubiquitination and enhancing cell cycle progression. These findings suggest that PSMD12 is a promising molecular target for future LUAD therapies.