CircPTK2/PABPC1/SETDB1 axis promotes EMT-mediated tumor metastasis and gemcitabine resistance in bladder cancer

Bladder cancer (BCa), characterized by high invasion, metastasis, recurrence, and chemoresistance, is one of the most prevalent urologic malignant tumors. Recent studies have highlighted the potential impact of the circRNAs-protein complex in tumorigenesis. However, the mechanisms by which the circRNAs-protein complex regulates BCa metastasis and chemoresistance remain elusive. Herein, we identified an upregulated circRNA, circPTK2, which could regulate SETDB1 expression by analyzing the transcriptome by RNA-sequencing. Importantly, using circRNA pulldown assay and RNA-binding protein immunoprecipitation, we identified PABPC1 as a robust novel interacting protein of circPTK2. Mechanistically, circPTK2 could bind to PABPC1 and enhance its ability to stabilize SETDB1 mRNA, thereby specifically promoting SETDB1 expression and facilitating SETDB1-mediated epithelial-mesenchymal transition (EMT). Functionally, overexpression of the circPTK2-SETDB1 axis markedly promoted migration, invasion, and gemcitabine resistance in vitro and enhanced lymph node metastasis in vivo. Collectively, our findings clarified a hitherto unexplored mechanism of the circPTK2/PABPC1/SETDB1 axis in EMT-mediated tumor metastasis and gemcitabine resistance in BCa.