m6A-mediated circG3BP1 translocation to stress granules promotes nucleation and senescence-linked chemoresistance

Abstract

RNAs and RNA-binding proteins (RBPs) play crucial roles in stress granule (SG) dynamics, yet the specific interactions between SG-associated circular RNAs (circRNAs) and RBPs in esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, we identified m6A-modified circG3BP1 as a potential prognostic biomarker in ESCC. Under cisplatin-induced stress, IGF2BPs facilitate the m6A-dependent translocation of circG3BP1 to SGs, where it functions as a scaffold to enhance TIAR-CAPRIN1 interactions, thereby promoting SG nucleation. SG formation suppresses the translation of senescence-associated mRNAs, such as p21, delaying chemotherapy-induced cellular senescence and contributing to cisplatin resistance in ESCC cells. Clinically, elevated circG3BP1 expression is associated with cisplatin resistance in patients with ESCC. These findings reveal a previously uncharacterized m6A-dependent mechanism by which circG3BP1 promotes SG-mediated chemoresistance, providing a promising potential biomarker and therapeutic target for ESCC treatment.

Keywords: CP: Cancer; CP: Molecular biology; chemoresistance; circG3BP1; esophageal cancer; m6A; senescence; stress granule.