Abstract
<title>Abstract</title> <p> Metastasis remains the principal cause of breast cancer–related mortality, and emerging evidence suggests that RNA-binding proteins (RBPs) can reprogram invasive behavior through the post-transcriptional control of cytoskeletal regulators. Cold-inducible RNA-binding protein (CIRBP) is expressed as long (CIRBP-L) and short (CIRBP-S) isoforms, but their individual roles in tumor metastasis are unclear. Here, we show that CIRBP-L, but not CIRBP-S, suppresses breast cancer cell migration, invasion, and <italic>in vivo</italic> lung colonization. CIRBP-L expression was significantly reduced in metastatic, high-grade, and basal-like tumors, and correlated with patient survival, whereas CIRBP-S was enriched in aggressive subtypes. Mechanistically, CIRBP-L directly bound to the N-terminal doublecortin (DCX) domain coding sequence of doublecortin-like kinase 1 long isoform (DCLK1-L) mRNA, enhancing its translation. DCLK1-L elevation stabilized microtubules by increasing α-tubulin K40 acetylation through the inhibition of glycogen synthase kinase 3β (GSK3β) activity, leading to reduced histone deacetylase 6 (HDAC6)–mediated α-tubulin deacetylation. Furthermore, genetic or pharmacological manipulation of DCLK1-L or HDAC6 confirmed that the CIRBP-L/DCLK1-L/GSK3β–HDAC6 axis is essential for microtubule stabilization and metastasis suppression. These findings identify CIRBP-L as an isoform-specific post-transcriptional regulator that restrains metastatic progression via microtubule stabilization and suggest that therapeutic targeting of the CIRBP-L/DCLK1-L axis could provide a novel strategy for advanced breast cancer. </p>