Circ0008399 Interaction with WTAP Promotes Assembly and Activity of the m6A Methyltransferase Complex and Promotes Cisplatin Resistance in Bladder Cancer.
Circ0008399 Interaction with WTAP Promotes Assembly and Activity of the m6A Methyltransferase Complex and Promotes Cisplatin Resistance in Bladder Cancer.
复制标题
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，并促进膀胱癌的顺铂耐药性。
DOI：
10.1158/0008-5472.can-21-1518
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发表时间：
2021-12-15
期刊：
影响因子：
11.2
通讯作者：
Jiang, Guosong
中科院分区：
文献类型：
--
作者：
Wei, Wenjie;Sun, Jiayin;Jiang, Guosong
顺铂（CDDP）为基础的化疗是一线治疗肌肉浸润性和转移性膀胱癌，但大多数患者迅速发展耐药。N6-甲基腺苷（m6 A）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，研究尚未完全阐明环状RNA（circRNA）是否可以直接调节mRNA的m6 A修饰。在这里，我们报告了一种新的circRNA，hsa_circ_0008399（circ 0008399），上调真核翻译起始因子4A 3（EIF 4A 3）在膀胱癌组织和细胞系。在功能上，circ 0008399抑制膀胱癌细胞的凋亡。在机制上，circ 0008399结合肾母细胞瘤1-相关蛋白（WTAP），以促进WTAP/胃L3/胃L14 m6 A甲基转移酶复合物的形成。Circ 0008399通过以m6 A依赖性方式增加其mRNA稳定性来增加TNF α诱导蛋白3（TNFAIP 3）的表达。在膀胱癌患者中，circ 0008399和WTAP的高表达与不良结局相关。重要的是，circ 0008399/WTAP/TNFAIP 3通路的激活降低了膀胱癌对CDDP的化疗敏感性，靶向circ 0008399/WTAP/TNFAIP 3轴增强了CDDP的疗效。总的来说，这些发现为circRNA介导的m6 A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。重要性：一种新鉴定的circRNA circ 0008399结合WTAP，通过m6 A修饰调节靶RNA的表达，降低膀胱癌中顺铂的敏感性，暗示靶向该轴的潜在治疗价值。
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.