Abstract 4040: p63 represses metabolic pathways in aggressive bladder cancer

Abstract Over half a million of people get bladder cancer (BLCA) each year worldwide with a third of all cases leading to death. Recent breakthroughs significantly improved early detection of BLCA, however little progress has been done to manage advanced invasive cancers since 1980s. Regulation of gene expression by key transcription factors governs multiple molecular pathways determining tumour evolution and selection. Here, we screen the transcription factors based on changes of their essentiality throughout bladder cancer evolution and identify p63 is a key factor. p63 is an oncogene in multiple epithelial tumours, however its expression is dramatically reduced in advanced BLCA, furthermore the loss of p63 is associated with a worse prognosis. Yet, little is known about p63 targetome in bladder cancer. In this work, we use transcriptomics, genome occupancy and chromatin accessibility assays to characterise global p63 targetome in BLCA in vitro along with bioinformatic analyses of gene expression in BLCA patients. We identify metabolism as a key pathway repressed by p63 during BLCA evolution and we show that activation of this pathway is associated with poor prognosis. In vitro, targeting of specific metabolic pathways induces cell death. Altogether, we identify an unexpected tumour-suppressive role for p63 in bladder cancer and propose novel therapeutic strategies for treatment of invasive BLCA. Citation Format: Artem Smirnov, Mariacristina Franzese Canonico, Damiano Barnaba, Maurizio Fanciulli, Alessandro Mauriello, Gerry Melino, Eleonora Candi. p63 represses metabolic pathways in aggressive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4040.