METTL18在HER2阴性乳腺癌的SRC依赖性致癌反应中充当表型调节剂
METTL18 functions as a Phenotypic Regulator in Src-Dependent Oncogenic Responses of HER2-Negative Breast Cancer
影响因子:10.00000
分区:生物学1区 Top / 生化与分子生物学2区
发表日期:2024
作者:
Han Gyung Kim, Ji Hye Kim, Kyung-Hee Kim, Byong Chul Yoo, Sung-Ung Kang, Young Bong Kim, Sangmin Kim, Hyun-June Paik, Jeong Eon Lee, Seok Jin Nam, Narayanan Parameswaran, Jeung-Whan Han, Balachandran Manavalan, Jae Youl Cho
摘要
甲基转移酶样（METTL）18在RPL3蛋白上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伸长。几项研究报告说，肌动蛋白聚合用作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，并证明了Mettl18在HER-2阴性乳腺癌转移中的重要性，我们在体外使用了生化，分子生物学和免疫学方法（乳腺肿瘤细胞系），体内（肿瘤内果模型）以及在人类乳房乳房肿瘤的样本中。乳腺癌患者中31个METTL系列基因和22种甲基转移酶的基因表达比较表明，在人类HER2阴性乳腺癌中，METTL18高度扩增。此外，HER2阴性乳腺癌患者的METTL18表达水平升高与预后不良有关。 METTL18的损失显着降低了体外和体内乳腺肿瘤细胞的转移性反应。从机械上讲，METTL18通过METTL18介导的RPL3甲基化在MDA-MB-231细胞中间接调节原始癌基因酪氨酸 - 蛋白激酶SRC及其下游分子的磷酸化，这也参与了HSP90整体和蛋白质水平。在共聚焦显微镜和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产生的SRC在酪氨酸419和酪氨酸530上磷酸化，具有激酶活性和致癌功能。因此，建议METTL18-HSP90-ACTIN-SRC调节轴在HER2阴性乳腺癌的转移性反应中起关键的致癌作用，并且可能是一个有前途的治疗靶点。
Abstract
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.