USF1-activated hsa_circ_0076691 induces oxaliplatin resistance via facilitating FGF9 expression in miR-589-3p-dependent manners

Abstract

Chemotherapeutic efficacy in colorectal cancer (CRC) is significantly hindered by the development of drug resistance. Emerging evidence indicates that circular RNAs (circRNAs) play pivotal roles in various cancer-related biological processes. Nonetheless, the specific role of circRNAs in oxaliplatin resistance in CRC remains largely unexplored. In this study, hsa_circ_0076691 (circ76691) overexpression was observed in the oxaliplatin-resistant CRC group and could predict poor prognosis. Functional analyses revealed that circ76691 attenuates oxaliplatin-induced apoptosis both in vitro and in vivo, thereby contributing to enhanced oxaliplatin resistance. Mechanistically, circ76691 transcriptionally downregulates miR-589–3p expression and acts as a molecular sponge for miR-589–3p, sequestering it from its downstream targets. Notably, fibroblast growth factor 9 (FGF9), identified as a downstream inhibitory target of miR-589–3p, is subsequently upregulated due to circ76691 activity. Furthermore, circ76691 expression is transcriptionally induced by USF1 through direct binding to its promoter region. Collectively, these findings elucidate the USF1/circ76691/miR-589–3p/FGF9 axis in inhibiting oxaliplatin-induced apoptosis, suggesting circ76691 as a potential therapeutic target to enhance the efficacy of platinum-based therapy.