METTL1 mediates m7G modification of PFKFB3 mRNA to promote radioresistance in esophageal cancer by affecting glycolytic metabolism.

BACKGROUND

Glycolysis can contribute to radiotherapy resistance in cancers. Methyltransferase-like protein-1 (METTL1) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) are oncogenes in esophageal cancer (EC). Herein, the interaction between METTL1 and PFKFB3 in regulating glycolysis and radioresistance in EC was explored.

METHODS

PFKFB3 and METTL1 mRNA and protein levels were determined by RT-qPCR and Western blot. Cell viability, apoptosis, invasion, migration, and stemness were respectively measured via cell counting kit-8 assay, flow cytometry, transwell assay, wound healing assay and sphere formation assay. Glycolytic metabolism was evaluated by glucose consumption, lactate production, ATP/ADP ratio, and seahorse assay. Radiotherapy resistance was assessed using cell survival assay. RNA immunoprecipitation was performed to confirm interaction between METTL1 and PFKFB3. PFKFB3 function in vivo was studied using xenograft tumor model in mice.

RESULTS

PFKFB3 was significantly up-regulated in radiation-treated EC cells. Downregulation of PFKFB3 impeded EC cell viability, invasion, migration, stemness. PFKFB3 knockdown suppressed glycolysis to reduce radiation resistance of EC cells. METTL1 could enhance PFKFB3 mRNA stability by mediating the m7G modification of PFKFB3. METTL1 facilitated cell development, glycolysis and radioresistance via promoting PFKFB3. Radioresistance of EC was also decreased after silence of PFKFB3 in vivo.

CONCLUSION

This study evidenced that METTL1 induced m7G modification to stabilize PFKFB3 mRNA that further enhanced radiation resistance in EC via stimulating glycolysis.