Oncogenic epigenetic factor EP300 is a potential therapeutic target for bladder carcinoma.

Bladder cancer remains a major cause of global mortality with limited therapies. Here, we reported that epigenetic regulator EP300 acts as oncogenic role in bladder cancer. Public data show EP300 mutations correlated with better prognosis, while high EP300 expression predicted poor outcomes. Our clinical cohort demonstrated that EP300 expressed higher in tumors rather than adjacent tissues. Functionally, impairing of EP300 decreased both cell viability and organoids growth in bladder cancer cells. The selective EP300 inhibitor A485 similarly reduced bladder cancer cell growth in vitro and in vivo. Long-term treatment of A485 alleviated tumor invasion in a BBN-induced spontaneous bladder cancer mouse model. Bioinformatic analysis evaluated both basal/squamous-like markers and papillary-like markers were decreased in A485 treatment. Furthermore, downregulated genes by A485 are mainly related to cell cycle regulation. Mechanistically, A485 decreased the levels of EP300 and H3K27ac upon MYC enhancer, consequently inhibited MYC expression. Additionally, the MYC inhibitor demonstrated similar effects as A485 to decrease cell viability and organoid growth. Critically, in patient-derived organoids (PDOs), A485 selectively attenuated tumor organoid growth and reduced MKI67+ and CD44+ cell populations, sparing adjacent normal tissue organoids. Collectively, EP300 promotes bladder cancer progression by sustaining proliferation through MYC regulation, and its inhibitor A485 represents a promising targeted therapeutic candidate.