The METTL3-m⁶A-YTHDC1-AMIGO2 axis contributes to cell proliferation and migration in esophageal squamous cell...

The upregulation of methyltransferase-like 3 (METTL3) has been associated with the progression of esophageal cancer. However, METTL3-induced N⁶-methyladenosine (m⁶A) alterations on the downstream target mRNAs in esophageal squamous cell carcinoma (ESCC) are not yet fully understood. Our study revealed that silencing METTL3 resulted in a significant decrease in ESCC cell proliferation and metastasis in vitro and in vivo. Additionally, the adhesion molecule with Ig like domain 2 (AMIGO2) was identified as a potential downstream target of both METTL3 and YTH Domain-Containing Protein 1 (YTHDC1) in ESCC cells. Functionally, AMIGO2 augmented the malignant behaviors of ESCC cells in vitro and in vivo, and its overexpression can rescue the inhibition of the proliferation and migration in ESCC cells induced by METTL3 or YTHDC1 knockdown. Furthermore, our findings revealed that knockdown of METTL3 decreased m⁶A modification in the 5'-untranslated regions (5'UTR) of AMIGO2 precursor mRNA (pre-mRNA), and YTHDC1 interacted with AMIGO2 pre-mRNA to regulate AMIGO2 expression by modulating the splicing process of AMIGO2 pre-mRNA in ESCC cells. These findings highlighted a novel role of the METTL3-m⁶A-YTHDC1-AMIGO2 axis in regulating ESCC cell proliferation and motility, suggesting its potential as a therapeutic target for ESCC.