METTL3 antagonizes 5-FU chemotherapy and confers drug resistance in colorectal carcinoma

Colorectal cancer (CRC) is one of top five leading causes of cancer-associated mortalities worldwide. 5-Fluorouracil (5-FU) is the first-line chemotherapeutic drug in the treatment of CRC; however, its antineoplastic efficiency is limited due to acquired drug resistance. The regulatory mechanism underlying 5-FU chemotherapeutic response and drug resistance in CRC remains largely unknown. The present study identified that silencing of methyltransferase-like 3 (METTL3) suppressed the proliferation and migration of CRC HCT-8 cells. Using cell survival assays, flow cytometric and colony formation analyses, it was revealed that inhibition of METTL3 sensitized HCT-8 cells to 5-FU by enhancing DNA damage and inducing apoptosis in HCT-8 cells under 5-FU treatment. Furthermore, the expression of METTL3 was upregulated in 5-FU-resistant CRC cells (HCT-8R), which contributed to drug resistance through regulation of RAD51 associated Protein 1 (RAD51AP1) expression. Western blotting, immunofluorescence staining and drug sensitivity assays demonstrated that knockdown of METTL3 augmented 5-FU-induced DNA damage and overcame 5-FU-resistance in HCT-8R cells, which could be mimicked by inhibition of RAD51AP1. The present study revealed that the METTL3/RAD51AP1 axis plays an important role in the acquisition of 5-FU resistance in CRC, and targeting METTL3/RAD51AP1 may be a promising adjuvant therapeutic strategy for patients with CRC, particularly for those with 5-FU-resistant CRC.