PRDM1 restricts bladder cancer progression and enhances chemosensitivity by suppressing OTUD6A-mediated deubiquitination of CDC6.

PR domain zinc finger protein 1 (PRDM1) functions as a critical transcriptional repressor. The role of PRDM1 in various tumors is controversial, and its specific mechanism in bladder cancer (BCa) remains unclear. In the present study, we demonstrated that PRDM1 expression is downregulated in both human BCa tissues and BBN-induced mouse models of BCa. Gain- and loss-of-function experiments revealed that PRDM1 delays cell cycle progression, suppresses BCa cell proliferation, and enhances chemosensitivity, whereas PRDM1 knockdown promotes cell proliferation and induces chemoresistance. Ovarian tumor deubiquitinase 6 A (OTUD6A) is a deubiquitinating enzyme that prevents the proteasomal degradation of CDC6. PRDM1 directly binds to the OTUD6A promoter and suppresses its transcription, thereby reducing CDC6 deubiquitination and promoting its degradation. Knockdown of CDC6 or OTUD6A abrogates the protective effects of PRDM1 both in vitro and in vivo. Consistently, PRDM1 expression is negatively correlated with CDC6 and OTUD6A expression in BCa tissues. Collectively, these findings demonstrate that PRDM1 acts as a tumor suppressor in BCa by inhibiting OTUD6A transcription and promoting CDC6 degradation. We propose a PRDM1‒OTUD6A‒CDC6 axis model, providing novel insights into PRDM1 as a potential therapeutic target in BCa.