Deciphering p63-governed transcriptional programs in bladder cancer: novel links to lipid metabolism and lncRNAs

Urothelial carcinoma, the predominant histological subtype of bladder cancer (BLCA), is the most common malignancy of the urinary system. According to GLOBOCAN 2022 estimates, this tumor affects approximately 600.000 people each year and leads to the death of about a third of patients with advanced-stage tumors. The molecular and histological heterogeneity of this tumor represents a hard challenge for developing targeted and effective therapies. p63 is a transcription factor that plays a crucial role in epithelial development and differentiation. While it is frequently overexpressed in most epithelial tumors, acting as an oncogene, its expression in BLCA progressively decreases with tumor progression, and its loss is associated with a poor outcome in patients. However, the molecular mechanisms underlying the role of p63 in BLCA remain incompletely understood. In this study, we investigated the transcriptional program driven by p63 in BLCA, integrating RNAseq, ChIPseq, ATACseq, proteomics, lipidomics and functional analyses. We found that p63 represses a transcriptional program associated with lipid metabolism in low-stage BLCA cells. Among the identified targets, we found that p63 binds a promoter region of the gene that encodes the monoacylglycerol lipase (MGLL), repressing its expression through epigenetic mechanisms involving chromatin accessibility and histone acetylation. Interestingly, functional studies revealed that MGLL promotes cell invasion, lipid metabolism reprogramming and mitochondrial respiration in high-stage BLCA cells. Furthermore, we identified the long non-coding RNA LEADR as a p63-direct transcriptional target and showed that the p63– LEADR axis represses interferon-related pathways. Collectively, our findings identify novel p63-dependent regulatory networks involved in BLCA progression and provide a robust multi-omics resource available for future investigations on p63 biology in this tumor.