Department of Pathology, Xuzhou Medical University, 209 Tong-shan Road, Xuzhou, 221004, Jiangsu, China.
Department of Oncological Radiotherapy, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Oncogene. 2022 Sep;41(39):4420-4432. doi: 10.1038/s41388-022-02435-2. Epub 2022 Aug 20.
N6-methyladenosine (m6A) is the most abundant chemical modification on mRNA and plays significant roles in many bioprocesses. However, the functions of m6A on cervical cancer (CC) tumorigenesis remain unclear. Here we found methyltransferase-like 3 (METTL3), a core member of the m6A methyltransferase family, was greatly upregulated as an independent prognostic factor in CC. Mechanistically, the transcription factor ETS1 recruited P300 and WDR5 which separately mediated H3K27ac and H3K4me3 histone modification in the promoter of METTL3 and induced METTL3 transcription activation. Furthermore, we identified TXNDC5 as a target of METTL3-mediated m6A modification through MeRIP-seq, and revealed that METTL3-mediated TXNDC5 expression relied on the m6A reader-dependent manner. Functionally, we verified that METTL3 promoted proliferation and metastasis of CC cells by regulating of TXNDC5 expression through in vitro and in vivo experiments. In addition, our study verified the effect of METTL3/TXNDC5 axis on ER stress. Taken together, METTL3 facilitates the malignant progression of CC, suggesting that METTL3 might be a potential prognostic biomarker and therapeutic target for CC.
N6-甲基腺苷（m6A）是 mRNA 上最丰富的化学修饰物，在许多生物过程中发挥着重要作用。然而，m6A 在宫颈癌（CC）发生中的作用尚不清楚。在这里，我们发现甲基转移酶样 3（METTL3）作为 m6A 甲基转移酶家族的核心成员，作为一个独立的预后因素在 CC 中被极大地上调。在机制上，转录因子 ETS1 招募 P300 和 WDR5，它们分别介导 METTL3 启动子中的 H3K27ac 和 H3K4me3 组蛋白修饰，并诱导 METTL3 转录激活。此外，我们通过 MeRIP-seq 鉴定出 TXNDC5 是 METTL3 介导的 m6A 修饰的靶标，并揭示了 METTL3 介导的 TXNDC5 表达依赖于 m6A 阅读器的方式。功能上，我们通过体外和体内实验证实，METTL3 通过调节 TXNDC5 的表达促进 CC 细胞的增殖和转移。此外，我们的研究还验证了 METTL3/TXNDC5 轴对 ER 应激的影响。综上所述，METTL3 促进了 CC 的恶性进展，提示 METTL3 可能是 CC 的一个有潜力的预后标志物和治疗靶点。
