The METTL3/TRAP1 Axis as a Key Regulator of 5-Fluorouracil Chemosensitivity in Colorectal Cancer

Abstract

Abstract 5-Fluorouracil (5-FU) stands as the frontline chemotherapeutic for colorectal cancer (CRC). However, the enduring challenge of chemoresistance to 5-FU persists in clinical practice, and the precise regulatory mechanisms governing 5-FU response and resistance in CRC remain elusive. This study aims to investigate the role and mechanisms of METTL3 in regulating 5-FU chemosensitivity in CRC cells. Practically, 5-FU treatment not only hindered cell viability and induced apoptosis but also led to a reduction in METTL3 expression in HCT-116 and HCT-8 cells. Through a range of assays including drug sensitivity, EdU, colony formation, TUNEL staining, and flow cytometry, we unveiled that METTL3 depletion heightened 5-FU sensitivity and augmented apoptosis induction in vitro and in vivo. Conversely, METTL3 overexpression conferred HCT-116 and HCT-8 cells with resistance to 5-FU. Mechanistically, METTL3 regulates 5-FU sensitivity and apoptosis induction by modulating TRAP1 expression. Further, m6A colorimetric ELISA and MeRIP-qPCR assays demonstrated that METTL3 regulated TRAP1 expression in an m6A-dependent manner. Furthermore, the overexpression of TRAP1 mitigated the cytotoxic effects of 5-FU on HCT-116 and HCT-8 cells. In conclusion, this study uncovers the pivotal role of the METTL3/TRAP1 axis in modulating 5-FU chemosensitivity in CRC.