甲基转移酶样 (METTL)18 对 RPL3 蛋白具有组氨酸甲基转移酶活性，并参与核糖体生物合成和翻译延伸。多项研究报道肌动蛋白聚合作为 Src 调节剂，HSP90 参与形成聚合肌动蛋白束。为了了解 METTL18 在乳腺癌中的作用并证明 METTL18 在 HER-2 阴性乳腺癌转移中的重要性，我们使用了体外（乳腺肿瘤细胞系）、体内（肿瘤异种移植模型）的生物化学、分子生物学和免疫学方法）以及人类乳腺肿瘤样本。对乳腺癌患者中31个METTL系列基因和22个甲基转移酶的基因表达比较发现，METTL18在人HER2阴性乳腺癌中高度扩增。此外，HER2阴性乳腺癌患者METTL18表达水平升高与预后不良相关。 METTL18的缺失显着降低了乳腺肿瘤细胞在体外和体内的转移反应。从机制上讲，METTL18通过METTL18介导的RPL3甲基化间接调节MDA-MB-231细胞中原癌基因酪氨酸蛋白激酶Src及其下游分子的磷酸化，这也参与确定HSP90完整性和蛋白质水平。在共焦显微镜和 F/G-肌动蛋白测定中，发现 METTL18 通过 HSP90 诱导肌动蛋白聚合。涉及 METTL18、RPL3、HSP90 和肌动蛋白聚合的分子事件导致 Src 在酪氨酸 419 和酪氨酸 530 处磷酸化，具有激酶活性和致癌功能。因此，表明 METTL18-HSP90-Actin-Src 调节轴在 HER2 阴性乳腺癌的转移反应中发挥着关键的致癌作用，并且可能是一个有前途的治疗靶点。© 作者。

Methyltransferase-like (METTL)18 has histidine methyltransferase activity on the RPL3 protein and is involved in ribosome biosynthesis and translation elongations. Several studies have reported that actin polymerization serves as a Src regulator, and HSP90 is involved in forming polymerized actin bundles. To understand the role of METTL18 in breast cancer and to demonstrate the importance of METTL18 in HER-2 negative breast cancer metastasis, we used biochemical, molecular biological, and immunological approaches in vitro (breast tumor cell lines), in vivo (tumor xenograft model), and in samples of human breast tumors. A gene expression comparison of 31 METTL series genes and 22 methyltransferases in breast cancer patients revealed that METTL18 is highly amplified in human HER2-negative breast cancer. In addition, elevated levels of METTL18 expression in patients with HER2-negative breast cancer are associated with poor prognosis. Loss of METTL18 significantly reduced the metastatic responses of breast tumor cells in vitro and in vivo. Mechanistically, METTL18 indirectly regulates the phosphorylation of the proto-oncogene tyrosine-protein kinase Src and its downstream molecules in MDA-MB-231 cells via METTL18-mediated RPL3 methylation, which is also involved in determining HSP90 integrity and protein levels. In confocal microscopy and F/G-actin assays, METTL18 was found to induce actin polymerization via HSP90. Molecular events involving METTL18, RPL3, HSP90, and actin polymerization yielded Src phosphorylated at both tyrosine 419 and tyrosine 530 with kinase activity and oncogenic functions. Therefore, it is suggested that the METTL18-HSP90-Actin-Src regulatory axis plays critical oncogenic roles in the metastatic responses of HER2-negative breast cancer and could be a promising therapeutic target.© The author(s).