N6-methyladenosine (m6A) 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 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 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.
N6-methyladenosine (m6A) 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 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 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.
N6-methyladenosine (m6A) 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 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 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.
Alpha-ketoglutarate (α-KG)-dependent dioxygenases are a superfamily of enzymes that require oxygen, reduced iron and α-ketoglutarate for their catalytic functions. Therefore, they have the potential to sense the availabilities of oxygen, iron and specific metabolites, including α-KG and its structurally related metabolites. These enzymes play essential roles in various biological processes, including cellular adaptation to hypoxia, epigenetic and epitranscriptomic regulation of gene expression, and metabolic reprogramming. Many α-KG-dependent dioxygenases are dysregulated in cancer pathogenesis. Herein, we review how they are regulated and function in breast cancer, which may offer new therapeutic intervention strategies for targeting this family of enzymes.
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