Targeting YTHDF1 effectively re-sensitizes cisplatin-resistant colon cancer cells by modulating GLS-mediated glutamine metabolism

Colorectal cancer (CRC) has a high mortality rate and poor prognosis. Despite chemotherapeutic agents such as cisplatin, which has achieved a better prognosis and survival rate against cancer, drug resistance leads to significant challenges. Accumulating evidence suggests that YTHDF1, the N6-methyladenosine (m6A) “reader,” is an important regulator in tumor progresses. Herein, we report that YTHDF1 was significantly upregulated in human colon tumors and cell lines. Overexpression of YTHDF1 decreased the cisplatin sensitivity of colon cancer cells. From the established cisplatin-resistant CRC cell line (LoVo CDDP R), we detected that YTHDF1 was significantly upregulated in cisplatin-resistant CRC cells. Intriguingly, RNA sequencing (RNA-seq) results revealed that glutamine metabolism enzymes were clearly upregulated in LoVo CDDP R cells. Glutamine uptake, that is, glutaminase (GLS) activity, was upregulated in LoVo CDDP R cells. Furthermore, bioinformatics analysis indicated that the 3′ UTR of GLS1 contained a putative binding motif of YTHDF1, and an interaction was further validated by a protein-RNA interaction assay (RNA immunoprecipitation [RIP]). Furthermore, we demonstrated that YTHDF1 promoted protein synthesis of GLS1. Inhibiting GLS1 effectively synergizes with cisplatin to induce colon cancer cell death. Finally, that YTHDF1 mediated cisplatin through the GLS1-glutamine metabolism axis was validated by an in vivo xenograft mouse model. In summary, our study reveals a new mechanism for YTHDF1-promoted cisplatin resistance, contributing to overcoming chemoresistant colon cancers. [Display omitted] YTHDF1 is positively associated with cisplatin resistance through promoting glutamine metabolism, which is elevated in cisplatin-resistant CRC cells. YTHDF1 binds to the 3′ UTR of glutaminase 1 (GLS1) to promote protein synthesis of GLS1. Silencing the YTHDF1-mediated GLS1 and glutamine metabolism re-sensitizes cisplatin-resistant CRC cells in vitro and in vivo.