JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA
JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA
复制标题
JNK信号通过调节METTL3介导的PD-L1 mRNA m6A修饰促进膀胱癌免疫逃逸
DOI：
10.1158/0008-5472.can-21-1323
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发表时间：
2022-05-01
期刊：
影响因子：
11.2
通讯作者：
Li, Yang
中科院分区：
文献类型：
--
作者：
Ni, Zegui;Sun, Pengli;Li, Yang
RNA N-6-甲基腺苷(m(6)A)编写者甲基转移酶样3(METTL3)在许多类型的癌症中上调，并通过增加几个癌基因的表达来促进癌症的进展。因此，更好地了解METTL3在癌细胞中表达的调控机制和关键靶点，将为肿瘤的治疗提供新的靶点。在这项研究中，我们发现激活的JNK信号与膀胱癌中METTL3的表达增加有关。敲除JNK1或给予JNK抑制剂会削弱c-jun与METTL3启动子的结合，从而降低METTL3的表达和全局RNA m(6)A水平。此外，RNA m(6)A测序表明，m(6)A在免疫检查点PD-L1mRNA的3‘-UTR区富含m(6)A，这可以被m(6)A阅读器IGF2BP1识别，以调节RNA的稳定性和PD-L1的表达水平。抑制JNK信号转导抑制PD-L1mRNA中m6A的丰度，导致PD-L1表达下降。在功能上，METTL3是膀胱癌细胞通过调节PD-L1的表达来抵抗CD8(+)T细胞的细胞毒作用所必需的。此外，在体外和体内，JNK信号以METTL3依赖的方式促进肿瘤免疫逃逸。这些数据揭示了JNK/METTL3轴是膀胱癌m(6)A异常修饰和免疫调节的一种机制。意义：识别膀胱癌细胞逃避免疫系统的一种新的m(6)A依赖机制，揭示JNK信号是膀胱癌免疫治疗的潜在靶点。
The RNA N-6-methyladenosine (m(6)A) writer methyltransferase-like 3 (METTL3) is upregulated in many types of cancer and promotes cancer progression by increasing expression of several oncogenes. Therefore, a better understanding of the mechanisms regulating METTL3 expression and the key targets of METTL3 in cancer cells could provide new therapeutic targets. In this study, we found that activated JNK signaling is associated with increased METTL3 expression in bladder cancer. Knockdown of JNK1 or administration of a JNK inhibitor impaired the binding of c-Jun with the METTL3 promoter, thereby decreasing the expression of METTL3 and global RNA m(6)A levels. Moreover, RNA m(6)A sequencing indicated enrichment of m(6)A in the 3'-UTR of immune checkpoint PD-L1 mRNA, which could be recognized by the m(6)A reader IGF2BP1 to mediate RNA stability and expression levels of PD-L1. Inhibition of JNK signaling suppressed m6A abundance in PD-L1 mRNA, leading to decreased PD-L1 expression. Functionally, METTL3 was essential for bladder cancer cells to resist the cytotoxicity of CD8(+) T cells by regulating PD-L1 expression. Additionally, JNK signaling contributed to tumor immune escape in a METTL3-dependent manner both in vitro and in vivo. These data reveal the JNK/METTL3 axis as a mechanism of aberrant m(6)A modification and immune regulation in bladder cancer.Significance: The identification of a novel m(6)A-dependent mechanism underlying immune system evasion by bladder cancer cells reveals JNK signaling as a potential target for bladder cancer immunotherapy.[GRAPHICS]