METTL3 promotes peritoneal metastasis of colorectal cancer through regulating m6A modification of NRXN3 mRNA.

Colorectal cancer (CRC) is a prevalent digestive system malignancy accompanied by peritoneal metastasis occurring in 7% of cases. Methyltransferase-like 3 (METTL3) promoted the progression of CRC whereas its function in peritoneal metastasis was incompletely understood. Here, we found that METTL3 was upregulated in peritoneal metastasis tissues of CRC patients compared with CRC tissues. By sequencing the mRNA of above tissues, we discovered that METTL3-mediated N6-methyladenosine (m6A) modification regulated the downstream target neurexin-3 (NRXN3). NRXN3 promoted CRC peritoneal metastasis in vivo. Mechanically, we further verified the specific methylation sites of NRXN3 mRNA modified by METTL3. Functional cellular assays demonstrated METTL3-mediated upstream regulation of NRXN3. We also demonstrated that YTHDC1 is necessary for the METTL3-mediated stabilization of NRXN3 mRNA. Taken together, this study established a METTL3-YTHDC1-NRXN3 m6A modification-dependent regulation system in CRC peritoneal metastasis, suggesting potential candidates for peritoneal metastasis treatment.