m6A-modified circCREBBP enhances radiosensitivity of esophageal squamous cell carcinoma by reducing the stability of MYC through interaction with IGF2BP3.

Substantial evidence has showed a close relationship between circRNAs and m6A modification in tumorigenesis and development. However, limited research has explored the regulatory role and underlying mechanism of m6A-modified circRNAs in regulating the radiosensitivity of esophageal squamous cell carcinoma (ESCC). The aim of this study was to clarify the molecular pathway by which m6A-modified circCREBBP enhances the radiosensitivity of ESCC. Differentially expressed circRNAs were identified from radiosensitive and radioresistant ESCC tissues and cells, followed by methylated RNA immunoprecipitation analysis. The effects of these circRNAs on radiosensitivity were subsequently assessed. We identified that CircCREBBP is closely associated with m6A and radiosensitivity in ESCC. CircCREBBP expression was significantly reduced in ESCC patients resistant to concurrent radiochemotherapy. In vitro and in vivo experiments demonstrated that circCREBBP knockdown enhanced the ESCC radioresistance. Mechanistic investigations revealed that circCREBBP, modified by m6A, interacted with IGF2BP3 and competitively bound to it, thereby reducing MYC mRNA stability. This study identified circCREBBP as a new m6A-modified circRNA and confirmed the METTL3/IGF2BP3/circCREBBP/MYC axis as a potential therapeutic target in enhancing radiosensitivity in ESCC.