SPDEF promotes clear cell renal cell carcinoma progression by transcriptionally activating ELOVL2-mediated lipid metabolic reprogramming.

BACKGROUND: Characterized by cytoplasmic lipid accumulation and fatty-acid metabolic reprogramming, clear cell renal cell carcinoma (ccRCC) is closely related to tumor progression and invasion. The impact of SPDEF, an ETS transcription factor, in ccRCC and its involvement in lipid metabolism remain unclear.

METHODS: SPDEF expression and prognostic relevance were analyzed using TCGA-KIRC data and validated in ccRCC tissues and cell lines. Functional experiments were conducted to evaluate influence on cell proliferation, migration, lipid metabolism, and apoptosis. Regulatory interactions with ELOVL2 were examined via transcriptomic analysis, dual-luciferase reporter assays, ChIP-qPCR, and site-directed promoter mutagenesis.

RESULTS: SPDEF was significantly overexpressed and closed to higher TNM stage and unfavorable survival. The higher expression of SPDEF enhanced malignant phenotypes, increased lipid accumulation, and impeded apoptotic processes. Mechanistically, SPDEF bound to the -141 bp site of the ELOVL2 promoter, thereby activating its transcription; mutation of this site abolished activation. Altering ELOVL2 expression partially rescued or mimicked SPDEF-driven phenotypes.

CONCLUSIONS: SPDEF acts as an oncogenic transcriptional activator in ccRCC by directly upregulating ELOVL2, thereby driving lipid metabolic reprogramming and tumor progression. These findings provide mechanistic insight into the SPDEF-ELOVL2 axis in lipid-associated ccRCC progression, while its clinical and translational relevance requires further validation in larger patient cohorts and clinically relevant models.