METTL3 Facilitates Colorectal Carcinoma Progression via Regulating m6A-CRB3-Hippo Axis
Background Colorectal carcinoma (CRC) is the third most common cancer and the second most common cause of cancer-related death worldwide. RNA N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play an important role in cancer. However, the roles of m6A and METTL3 in CRC progression are still elusive. Methods Adenoma and CRC samples were applied to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate their associations with survival of CRC patients. The
... patients. The biological functions of METTL3 were investigated by CCK8, wound healing and transwell assays. M6A epitranscriptomic microarray, RNA stability and luciferase reporter assays were performed to explore the mechanism of METTL3 in CRC. Results m6A and METTL3 levels were significantly upregulated in both adenoma and CRC tissues, and the CRC patients with high m6A or METTL3 level had both shorter overall survival. METTL3 knockdown markedly inhibited the proliferation, migration and invasion of CRC cells. M6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown markedly inhibited the degradation of CRB3 mRNA to increase the CRB3 expression. In addition, CRB3 level was also markedly reduced in both adenoma and CRC tissues, and the CRC patients with high CRB3 level had higher overall survival and disease free survival. CRB3 knockdown significantly promoted the proliferation, migration and invasion of CRC cells. Finally, CRB3 knockdown inhibited Hippo pathway, and increased nuclear localization of YAP. Conclusions The m6A and METTL3 levels were significantly increased in both adenoma and CRC tissues. The CRC patients with high m6A or METTL3 levels had shorter overall survival. Mechanistically, METTL3 regulated the initiation and progression of CRC via regulating m6A-CRB3-Hippo pathway.