Cisplatin (CDDP)-based chemotherapy is the first-line treatment for muscle-invasive and metastatic bladder cancer, yet most patients rapidly develop resistance. N6-methyladenosine (m6A) 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 m6A modification of mRNA. Here we report upregulation of a novel circRNA, hsa\_circ\_0008399 ( circ0008399 ), by eukaryotic translation initiation factor 4A3 (EIF4A3) in bladder cancer tissues and cell lines. Functionally, circ0008399 inhibited apoptosis of bladder cancer cells. Mechanistically, circ0008399 bound Wilms' tumor 1–associating protein (WTAP) to promote formation of the WTAP/METTL3/METTL14 m6A methyltransferase complex. Circ0008399 increased expression of TNF alpha-induced protein 3 (TNFAIP3) by increasing its mRNA stability in an m6A-dependent manner. In patients with bladder cancer, high expression of circ0008399 and WTAP was associated with poor outcomes. Importantly, activation of the circ0008399 /WTAP/TNFAIP3 pathway decreased bladder cancer chemosensitivity to CDDP, and targeting the circ0008399 /WTAP/TNFAIP3 axis enhanced the CDDP efficacy. Collectively, these findings give novel insights into circRNA-mediated regulation of m6A modifications and provide potential therapeutic targets for bladder cancer. Significance: A newly characterized circRNA circ0008399 binds WTAP to modulate expression of target RNA through m6A modification and reduce cisplatin sensitivity in bladder cancer, implicating the potential therapeutic value of targeting this axis.

中文翻译：

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Circ0008399 与 WTAP 的相互作用促进 m6A 甲基转移酶复合物的组装和活性，并促进膀胱癌中的顺铂耐药

基于顺铂 (CDDP) 的化疗是肌肉浸润性和转移性膀胱癌的一线治疗方法，但大多数患者会迅速产生耐药性。N6-甲基腺苷（m6A）甲基化是一种普遍存在的RNA修饰，其在膀胱癌CDDP化疗敏感性调节中的具体作用和潜在机制尚不清楚。此外，研究还没有完全阐明环状RNA（circRNA）是否可以直接调节mRNA的m6A修饰。在这里，我们报告了膀胱癌组织和细胞系中真核翻译起始因子 4A3 (EIF4A3) 对新型 circRNA hsa\_circ\_0008399 (circ0008399) 的上调。在功能上，circ0008399 抑制膀胱癌细胞的凋亡。机械地，circ0008399 绑定 Wilms' 肿瘤 1 相关蛋白 (WTAP) 以促进 WTAP/METTL3/METTL14 m6A 甲基转移酶复合物的形成。Circ0008399 通过以 m6A 依赖性方式增加其 mRNA 稳定性来增加 TNF α 诱导蛋白 3 (TNFAIP3) 的表达。在膀胱癌患者中，circ0008399 和 WTAP 的高表达与不良预后相关。重要的是，circ0008399 /WTAP/TNFAIP3 通路的激活降低了膀胱癌对 CDDP 的化学敏感性，靶向 circ0008399 /WTAP/TNFAIP3 轴增强了 CDDP 疗效。总的来说，这些发现为 circRNA 介导的 m6A 修饰调控提供了新的见解，并为膀胱癌提供了潜在的治疗靶点。意义：