RESUMEN
Colorectal cancer (CRC) is one of top five leading causes of cancerassociated mortalities worldwide. 5Fluorouracil (5FU) is the firstline chemotherapeutic drug in the treatment of CRC; however, its antineoplastic efficiency is limited due to acquired drug resistance. The regulatory mechanism underlying 5FU chemotherapeutic response and drug resistance in CRC remains largely unknown. The present study identified that silencing of methyltransferaselike 3 (METTL3) suppressed the proliferation and migration of CRC HCT8 cells. Using cell survival assays, flow cytometric and colony formation analyses, it was revealed that inhibition of METTL3 sensitized HCT8 cells to 5FU by enhancing DNA damage and inducing apoptosis in HCT8 cells under 5FU treatment. Furthermore, the expression of METTL3 was upregulated in 5FUresistant CRC cells (HCT8R), 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 5FUinduced DNA damage and overcame 5FUresistance in HCT8R 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 5FU resistance in CRC, and targeting METTL3/RAD51AP1 may be a promising adjuvant therapeutic strategy for patients with CRC, particularly for those with 5FUresistant CRC.