Zhao Wei, Cui Yameng, Liu Lina, Ma Xiaozhou, Qi Xiaoqian, Wang Yue, Liu Zihao, Ma Shiqing, Liu Jingwen, Wu Jie
The School and Hospital of Stomatology, Tianjin Medical University, Tianjin 300070, China.
Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Mol Ther Nucleic Acids. 2020 Jun 5;20:1-12. doi: 10.1016/j.omtn.2020.01.033. Epub 2020 Feb 4.
N-Methyladenosine (mA) is the most common internal modification of eukaryotic messenger RNA (mRNA) that occurred on the N nitrogen of adenosine. However, the roles of mA in oral squamous cell carcinoma (OSCC) are still elusive. Here, we investigate the function and mechanism of methyltransferase-like 3 (METTL3) in OSCC tumorigenesis. Clinically, METTL3 was significantly upregulated in tissue samples and correlated with the poor prognosis of OSCC patients. Functionally, loss and gain studies illustrated that METTL3 promoted the proliferation, invasion, and migration of OSCC cells in vitro, and METTL3 knockdown inhibited tumor growth in vivo. Mechanistically, methylated RNA immunoprecipitation sequencing (MeRIP-seq) illustrated that METTL3 targeted the 3' UTR (near to stop codon) of the c-Myc transcript to install the mA modification, thereby enhancing its stability. Furthermore, results revealed that YTH N-methyladenosine RNA binding protein 1 (YTH domain family, member 1 [YTHDF1]) mediated the mA-increased stability of c-Myc mRNA catalyzed by METTL3. In conclusion, our findings herein identify that METTL3 accelerates the c-Myc stability via YTHDF1-mediated mA modification, thereby giving rise to OSCC tumorigenesis.
N-甲基腺苷（mA）是真核生物信使核糖核酸（mRNA）最常见的内部修饰，发生在腺苷的N氮原子上。然而，mA在口腔鳞状细胞癌（OSCC）中的作用仍不清楚。在此，我们研究了甲基转移酶样3（METTL3）在OSCC肿瘤发生中的功能和机制。临床上，METTL3在组织样本中显著上调，且与OSCC患者的不良预后相关。在功能上，缺失和增益研究表明，METTL3在体外促进了OSCC细胞的增殖、侵袭和迁移，而敲低METTL3则在体内抑制了肿瘤生长。从机制上来说，甲基化RNA免疫沉淀测序（MeRIP-seq）表明，METTL3靶向c-Myc转录本的3'非翻译区（靠近终止密码子）以进行mA修饰，从而增强其稳定性。此外，结果显示YTH N-甲基腺苷RNA结合蛋白1（YTH结构域家族成员1 [YTHDF1]）介导了METTL3催化的c-Myc mRNA稳定性增加。总之，我们的研究结果表明，METTL3通过YTHDF1介导的mA修饰加速了c-Myc的稳定性，从而引发了OSCC的肿瘤发生。
