SPDEF-mediated BIRC5 transcriptional activation enhances non-small cell lung cancer progression

SAM-pointed domain-containing ETS transcription factor (SPDEF), an ETS family transcription factor (TF), functions as a tumor-promoting factor in non-small cell lung cancer (NSCLC). However, the precise mechanisms of SPDEF in regulating NSCLC pathogenesis remain to be fully characterized.

Bioinformatics analyses were used to identify disease-associated TFs and downstream targets. A protein-protein interaction (PPI) network was constructed to predict hub TFs. The relationship between SPDEF and BIRC5 was validated by luciferase and ChIP assays. The influences on cell phenotypes were evaluated by testing cell colony formation, invasion, migration, and apoptosis. Xenograft studies were used to explore the role in tumor growth.

This study revealed 101 disease-associated TFs in NSCLC. GO enrichment analysis of these TFs demonstrated significant enrichment in biological processes including lung development, lung differentiation, and Wnt signaling pathway. PPI analysis revealed FOXA1, GATA6, TBX2, and SPDEF as core regulatory factors. SPDEF and BIRC5 levels were upregulated in NSCLC tumors and cell lines. Mechanistically, SPDEF induced BIRC5 upregulation through transcriptional regulation. SPDEF depletion impaired NSCLC cell invasion, migration, and clonogenicity while inducing apoptosis in vitro, which could be abolished by BIRC5 reconstitution. Moreover, SPDEF deficiency inhibited A549 tumor growth in subcutaneous xenograft models. Additionally, BIRC5 activated the Wnt/β-catenin pathway in NSCLC cells.

Our findings demonstrate the tumor-promoting function of SPDEF in NSCLC by transcriptionally activating BIRC5, highlighting SPDEF as a candidate target for future NSCLC-directed therapies.