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

TL;DR

PRDM1 limits bladder cancer growth and improves treatment response by reducing CDC6 levels through suppression of OTUD6A activity.

Contribution

The study identifies a PRDM1-OTUD6A-CDC6 regulatory axis in bladder cancer, revealing a novel tumor suppressive mechanism.

Findings

PRDM1 is downregulated in bladder cancer tissues and mouse models.

PRDM1 suppresses cell proliferation and enhances chemosensitivity by inhibiting OTUD6A-mediated CDC6 deubiquitination.

PRDM1 expression is negatively correlated with OTUD6A and CDC6 in bladder cancer tissues.

Abstract

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.

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