Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
Elife. 2023 Aug 17;12:RP87283. doi: 10.7554/eLife.87283.
-methyladenosine (mA) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3). We find that METTL3a is required for the METTL3-WTAP interaction, RNA mA deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of mA sequencing data shows that depletion of METTL3a globally disrupts mA deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via mA-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.
RNA 的 -m6A 甲基化由甲基转移酶复合物（MTC）完成，其核心组件包括 METTL3-METTL14 异二聚体和 WTAP，促进了乳腺癌的发生，但潜在的调控机制仍不清楚。在这里，我们鉴定出一种新型的 METTL3a 裂解形式（METTL3 的残基 239-580）。我们发现 METTL3a 对于 METTL3-WTAP 相互作用、RNA m6A 沉积以及癌细胞增殖都是必需的。从机制上讲，我们发现 METTL3a 对于 METTL3-METTL3 相互作用是必需的，而这种相互作用是 WTAP 在 MTC 中募集的前提步骤。m6A 测序数据分析表明，METTL3a 的耗竭会导致 m6A 沉积的全面破坏，而 METTL3a 通过 m6A 介导的 TMEM127 表达抑制来介导哺乳动物雷帕霉素靶蛋白（mTOR）的激活。此外，我们发现 METTL3 的裂解是由 mTOR 依赖性蛋白酶体介导的，这揭示了 METTL3a 和 mTOR 信号之间的正反馈调节。我们的研究结果揭示了 METTL3a 是 MTC 的一个重要组成部分，并提示 METTL3a-mTOR 轴可能是乳腺癌的一个潜在治疗靶点。
