Interaction with WTAP Promotes Assembly and Activity of the mA Methyltransferase Complex and Promotes Cisplatin Resistance in Bladder Cancer.

Cisplatin (CDDP)-based chemotherapy is the first-line treatment for muscle-invasive and metastatic bladder cancer, yet most patients rapidly develop resistance. N6-methyladenosine (mA) methylation is a pervasive RNA modification, and its specific role and potential mechanism in the regulation of CDDP chemosensitivity in bladder cancer remain unclear. Furthermore, studies have not yet fully elucidated whether circular RNA (circRNA) can directly regulate mA modification of mRNA. Here we report upregulation of a novel circRNA, (), by eukaryotic translation initiation factor 4A3 (EIF4A3) in bladder cancer tissues and cell lines. Functionally, inhibited apoptosis of bladder cancer cells. Mechanistically, bound Wilms' tumor 1-associating protein (WTAP) to promote formation of the WTAP/METTL3/METTL14 mA methyltransferase complex. increased expression of TNF alpha-induced protein 3 (TNFAIP3) by increasing its mRNA stability in an mA-dependent manner. In patients with bladder cancer, high expression of and WTAP was associated with poor outcomes. Importantly, activation of the /WTAP/TNFAIP3 pathway decreased bladder cancer chemosensitivity to CDDP, and targeting the /WTAP/TNFAIP3 axis enhanced the CDDP efficacy. Collectively, these findings give novel insights into circRNA-mediated regulation of mA modifications and provide potential therapeutic targets for bladder cancer. SIGNIFICANCE: A newly characterized circRNA binds WTAP to modulate expression of target RNA through mA modification and reduce cisplatin sensitivity in bladder cancer, implicating the potential therapeutic value of targeting this axis.