A cleaved METTL3 potentiates the METTL3–WTAP interaction and breast cancer progression
Chaojun Yan, Jingjing Xiong, Zirui Zhou, Qifang Li, Chuan Gao, Mengyao Zhang, Liya Yu, Jinpeng Li, Ming-Ming Hu, Chen‐Song Zhang, Cheguo Cai, Haojian Zhang, Jing Zhang
Abstract
N 6 -methyladenosine (m 6 A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3–METTL14 heterodimers and Wilms’ tumor 1-associated protein (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 m 6 A 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 m 6 A sequencing data shows that depletion of METTL3a globally disrupts m 6 A deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via m 6 A-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.