ZNF503 reduces chemotherapy sensitivity in prostate cancer by activating ISL1 and Notch1 signaling

Prostate cancer (PCa) remains a leading cause of cancer-related mortality, with reduced sensitivity to chemotherapy significantly compromising treatment efficacy. The zinc finger protein 503 (ZNF503) has recently emerged as a potential regulator of cancer progression, but its role in prostate cancer and chemotherapy resistance has yet to be fully elucidated. In this study, we investigate the functional role of ZNF503 in prostate cancer and its involvement in mediating chemotherapy resistance. Using a combination of RNA sequencing, functional assays, and in vivo models, we demonstrate that ZNF503 expression is elevated in chemotherapy-resistant prostate cancer cells and tissues. ZNF503 overexpression enhances tumor cell proliferation, migration, and protects cells from chemotherapy -induced apoptosis following acute exposure to agents such as docetaxel and cisplatin. Mechanistically, we show that ZNF503 activates the Notch1 signaling pathway, a key driver of aggressive cancer phenotypes, and this effect is associated with increased expression of the transcription factor ISL1. Further analysis revealed that ISL1 is required for ZNF503-induced Notch1 activation. Knockdown of ISL1 significantly attenuates ZNF503-induced Notch1 expression and restores chemotherapy sensitivity, underscoring the critical role of the ZNF503-ISL1-Notch1 axis in prostate cancer progression and drug resistance. In clinical samples, high ZNF503 expression correlates with poor prognosis and reduced chemotherapy sensitivity, suggesting that ZNF503 is a candidate prognostic marker that requires further validation in larger, independent cohorts with multivariate analysis. Our findings provide novel insights into the molecular mechanisms underpinning chemotherapy resistance in prostate cancer and position ZNF503 as a promising therapeutic target to overcome drug resistance and improve patient outcomes.