DUSP4-mediated dephosphorylation of PSMD14 enhances PSMD14-dependent deubiquitination of MICALL2 and promotes malignant progression in clear cell renal cell carcinoma

BACKGROUND: PSMD14 has been identified as an oncogene in various cancers; however, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study investigated the effects of PSMD14 on ccRCC cell proliferation, migration, and invasion. METHODS: Thirty paired cancerous and adjacent non-cancerous tissues were collected from patients with ccRCC. The human normal renal tubular epithelial cell line HK-2 and ccRCC cell lines (KMRC-1, OS-RC-2, Caki-1, and 786-O) were used for in vitro experiments. The mRNA and protein expression levels of PSMD14, MICALL2, and DUSP4 were analyzed by RT-qPCR and Western blotting. Cell viability and proliferation were evaluated using the CCK-8 assay and EdU staining. Wound-healing and Transwell assays were performed to assess cell migration and invasion, respectively. Co-immunoprecipitation was conducted to verify molecular interactions between PSMD14 and MICALL2/DUSP4. Immunoprecipitation was used to examine MICALL2 ubiquitination and PSMD14 phosphorylation. An in vivo ccRCC mouse model was established to assess tumor growth. Immunohistochemical staining was used to detect Ki67 and PSMD14 expression in mouse kidney tissues. RESULTS: PSMD14 was significantly upregulated in ccRCC tissues and was correlated with poor patient outcomes. PSMD14 knockdown inhibited ccRCC cell proliferation, migration, and invasion. PSMD14 suppressed MICALL2 ubiquitination and degradation, thereby increasing MICALL2 expression and promoting ccRCC malignant progression. Dephosphorylation of PSMD14 by DUSP4 enhanced its interaction with MICALL2. Moreover, DUSP4-mediated dephosphorylation amplified the PSMD14-induced increase in MICALL2, further facilitating ccRCC progression. In vivo, PSMD14 knockdown inhibited ccRCC tumor development. CONCLUSION: DUSP4-mediated dephosphorylation of PSMD14 promotes ccRCC malignant progression by regulating MICALL2 deubiquitination, providing potential therapeutic targets for ccRCC treatment.