YTHDF2 alleviates the radioresistance of rectal cancer cells by targeting methylated MYC.

YTHDF2, a N6-methyladenosine (m6A) recognition protein, is involved in the occurrence and progression of various malignancies. The impact of YTHDF2 on the radiosensitivity of rectal cancer cells remains unclear. This study aimed to investigate the effect and potential mechanisms of YTHDF2 on radiotherapy sensitivity in rectal cancer. Acquired radioresistant colorectal cancer (CRC) cell lines (HCT-116-R and CX-1-R) were established through accumulative X-ray exposure. YTHDF2 was exogenously overexpressed or endogenously knocked down using lentivirus systems, and the radiosensitivity of the cells was analyzed both in vitro and in vivo. High-throughput transcriptome sequencing identified MYC as a downstream target of YTHDF2. RNA stability assays revealed that YTHDF2 facilitated the decay of MYC messenger (mRNA) through an m6A-dependent mechanism. Western blot analyses demonstrated that YTHDF2 modulated MYC expression and the Hippo signaling pathway, enhancing p-MST1/2, p-LATS1 and p-YAP levels while reducing nuclear YAP. Functional assays showed that YTHDF2 overexpression improved radiosensitivity by promoting radiation-induced apoptosis and G2/M phase arrest. MYC overexpression reversed these effects, suggesting a competitive regulatory relationship between YTHDF2 and MYC. These findings indicate that YTHDF2 modulates radiosensitivity through MYC and the Hippo signaling pathway. YTHDF2 enhances the radiosensitivity of rectal cancer cells by facilitating the degradation of MYC mRNA and activating the Hippo signaling pathway. Targeting YTHDF2 may provide a promising therapeutic strategy for overcoming radioresistance in rectal carcinoma.