DGKZ Promotes Tumor Progression in Bladder Cancer Cells by Modulating Phosphatidic Acid Biosynthesis through Interaction with CEBPZ Protein

Abstract

Diacylglycerol kinase ζ (DGKZ) plays a crucial role in converting diacylglycerol to phosphatidic acid, yet its specific involvement in bladder cancer (BCa) progression remains unclear. We utilized clinical samples from tissue microarrays and conducted Immunohistochemistry (IHC) staining to evaluate DGKZ expression in human bladder tissues. Cell growth, apoptosis, wound-healing, and invasion assays were performed to assess DGKZ’s impact on cell proliferation. Co-immunoprecipitation assays coupled with liquid chromatography-mass spectrometry explored DGKZ’s interactions with associated proteins. Analysis of the TCGA-BCa database revealed that elevated DGKZ expression correlates with tumor progression and poor prognosis in BCa patients, suggesting its potential as a pro-metastatic gene. Inhibition of DGKZ significantly reduced both in vitro and in vivo cell proliferation and invasion. Additionally, co-immunoprecipitation assays identified 1,743 potential protein interactors of DGKZ in T24 cells. Bioinformatics analysis and rescue experiments pinpointed CEBPZ as a DGKZ binding partner, with the interaction relying on DGKZ’s PDZ-binding motif in its C-terminus. Ectopic expression of CEBPZ countered the suppression of the Akt/mTOR pathway observed in DGKZ-knockdown BCa cells, thereby promoting phosphatidic acid biosynthesis. In conclusion, these findings underscore the significance of the DGKZ-CEBPZ interaction in BCa growth and pave the way for exploring therapeutic interventions targeting this interaction to inhibit DGKZ-mediated tumor growth in BCa.