STAU1-mediated stabilization of ITGB5 enhances FOXP3 transcriptional activity to form a self-reinforcing metastasis circuit in colorectal cancer.

Dysregulation of integrins plays an important role in cancer metastasis, but its underlying mechanisms remain largely unexplored. Here we report that the RNA-binding protein STAU1 enhances mRNA stability of integrin β5 (ITGB5), forming a self-perpetuating loop that drives colorectal cancer (CRC) metastasis. STAU1 was significantly upregulated in CRC, particularly in metastatic tissues, and correlated with poor patient outcomes. STAU1 knockdown suppressed CRC cell metastasis in vitro and in vivo, while its overexpression promoted metastasis. ITGB5 mRNA was identified as a novel target of STAU1 and mediated its pro-metastatic effects. Mechanistically, STAU1 directly bound the 3' untranslated region of ITGB5 mRNA to stabilize it. We further identified transcription factor FOXP3 as a downstream effector of ITGB5 in CRC cells. STAU1-mediated ITGB5 upregulation increased FOXP3 phosphorylation at serine 418, which enhanced FOXP3 binding to the STAU1 promoter and activated its transcription, establishing a STAU1-ITGB5-FOXP3 positive feedback loop. This loop was augmented in CRC specimens from patients with distant metastasis. Our study elucidates a novel RBP-integrin regulatory axis in CRC metastasis and proposes the STAU1-ITGB5-FOXP3 loop as a prognostic biomarker and promising therapeutic target for metastatic CRC.