Ningbo Institute of Life and Health Industry, Chinese Academy of Sciences, Ningbo, Zhejiang, The People's Republic of China.
Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, The People's Republic of China.
Cell Death Dis. 2023 Nov 25;14(11):765. doi: 10.1038/s41419-023-06287-w.
The role of METTL3-mediated N6-methyladenosine (mA) modification has been elucidated in several cancers, but the concrete mechanism underlying its function in colorectal cancer is still obscure. Here, we revealed that upregulated methyltransferase-like 3 (METTL3) in colorectal cancer exerted both methyltransferase activity-dependent and -independent functions in gene regulation. METTL3 deposited mA on the 3' untranslated region of the JAK1 transcript to promote JAK1 translation relying on YTHDF1 recognition. Besides, METTL3 was redistributed to the STAT3 promoter and worked in concert with NF-κB to facilitate STAT3 transcription, which was achieved independently on METTL3 methyltransferase activity. The increased JAK1 and STAT3 corporately contributed to the activation of the p-STAT3 signaling pathway and further upregulated downstream effectors expressions, including VEGFA and CCND1, which finally resulted in enhanced cancer cell proliferation and metastasis in vitro and in vivo. Collectively, our study revealed the unappreciated dual role of METTL3 as an mA writer and a transcription regulator, which worked together in the same signaling pathway to drive colorectal cancer malignancy.
METTL3 介导的 N6-甲基腺苷（m6A）修饰在几种癌症中作用已被阐明，但它在结直肠癌中的具体功能机制仍不清楚。在这里，我们揭示了结直肠癌中上调的甲基转移酶样 3（METTL3）在基因调控中发挥了依赖和不依赖甲基转移酶活性的功能。METTL3 将 mA 沉积在 JAK1 转录本的 3'非翻译区，以促进 JAK1 翻译，这依赖于 YTHDF1 的识别。此外，METTL3 被重新分配到 STAT3 启动子上，并与 NF-κB 协同作用促进 STAT3 转录，这是独立于 METTL3 甲基转移酶活性实现的。增加的 JAK1 和 STAT3 共同激活了 p-STAT3 信号通路，并进一步上调下游效应物的表达，包括 VEGFA 和 CCND1，最终导致体外和体内癌细胞增殖和转移增强。总之，我们的研究揭示了 METTL3 作为 mA 书写者和转录调节剂的未被认识的双重作用，它们在同一信号通路中协同作用，推动结直肠癌的恶性进展。
