TFAP2C drives cisplatin resistance in bladder cancer by upregulating YAP and activating β-catenin signaling

Cisplatin-based chemotherapy is a conventional therapy for muscle-invasive bladder cancer (BC); however, its efficacy is often limited by the emergence of resistance to cisplatin. Yes-associated protein (YAP) and β-catenin are involved in this resistance, yet their upstream regulators are not well defined. This study investigates the role of TFAP2C in regulating YAP expression and its impact on cisplatin resistance in BC. The Cancer Genome Atlas (TCGA) gene expression data and GSE231835 dataset were analyzed to identify potential transcription factors regulating YAP. Assessed TFAP2C and YAP expression in clinical samples and cell lines. Functional assays were performed following TFAP2C knockdown. Dual-luciferase reporter assays and Chromatin immunoprecipitation (ChIP) confirmed TFAP2C binding to the YAP promoter. A mouse model evaluated the effects of TFAP2C silencing on tumor growth and cisplatin resistance. The results showed that TFAP2C was identified as an upstream activator of YAP, with elevated expression in cisplatin-resistant BC cell lines and positive correlation with YAP expression. Silencing TFAP2C reduced malignant behaviors, decreased YAP, phosphorylated YAP (p-YAP) and β-catenin levels, and increased apoptosis in both cisplatin-sensitive and cisplatin-resistant BC cells. Besides, TFAP2C directly binds to the YAP promoter, enhancing its transcription. In the xenograft model, TFAP2C silencing significantly inhibited tumor growth and reduced cisplatin resistance. TFAP2C promotes cisplatin resistance and malignant behavior in BC by upregulating YAP and activating the β-catenin signaling pathway. Targeting TFAP2C offers a novel therapeutic strategy to overcome cisplatin resistance in BC, representing a new discovery in combating chemoresistance.