Hypoxia remodels circSTX6 nuclear export through URH49-ALYREF to drive IGF1-mediated bladder cancer progression

Although circRNAs are increasingly implicated in tumor biology, most studies emphasize expression changes while overlooking subcellular distribution. The mechanisms governing circRNA nuclear export in bladder cancer (BCa) and their contribution to progression are poorly defined.

Differential expressed circRNAs between BCa and adjacent tissues were identified through bioinformatic analysis. Oncologic phenotypes were assessed using CCK-8, colony-formation, transwell, EdU assays in vitro, and subcutaneous xenograft and tail-vein lung metastasis mouse models in vivo. The circSTX6 interactome and transcript-level effects were characterized by RNA-seq, RNA immunoprecipitation (RIP), RNA pull-down, and mass spectrometry. Hypoxia treatment, nuclear-cytoplasmic fractionation, and FISH were used to quantify circSTX6 subcellular localization and oxygen-dependent dynamics.

circSTX6 was upregulated in BCa tissues and cells and promoted malignant phenotypes both in vitro and in vivo. Hypoxia increased circSTX6 nuclear retention. Mechanistically, hypoxia induced KCMF1-mediated ubiquitination and degradation of URH49 while upregulating ALYREF, thereby impairing URH49-dependent circSTX6 nuclear export and further promoting circSTX6 nuclear retention. Nuclear-retained circSTX6 bound HNRNPA2B1 and stabilized IGF1 mRNA, activating a circSTX6/HNRNPA2B1/IGF1 axis that enhanced BCa proliferation and migration.

Hypoxia remodels circSTX6 nuclear export through URH49 degradation and ALYREF upregulation, resulting in circSTX6 nuclear retention and enhanced IGF1-mediated BCa progression.