A cleaved METTL3 potentiates the METTL3-WTAP interaction and breast cancer progression.

Abstract

<i>N</i>⁶-methyladenosine (m⁶A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and <i>Wilms' tumor 1-associated protein</i> (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 m⁶A 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 m⁶A sequencing data shows that depletion of METTL3a globally disrupts m⁶A deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via m⁶A-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.