FSCN1 regulates TGF-β signalling to promote esophageal squamous cell carcinoma metastasis via stabilizing THBS1 mRNA.

Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype of esophageal cancer worldwide, is a leading cause of cancer-related mortality. Although Fascin actin-bundling protein 1 (FSCN1), an actin family member, is well-characterized for its role in facilitating tumor cell migration and invasion through cytoskeletal remodeling, its function as an RNA-binding protein remains poorly understood. Here we show that FSCN1 directly interacts with THBS1 mRNA via its RNA-binding capacity, with the binding localized to the coding sequence region. Functionally, FSCN1 stabilizes THBS1 transcripts to enhance protein expression, thereby activating TGF-β signaling to drive ESCC metastasis in vivo and in vitro, utilizing esophageal cancer cell lines and subcutaneous xenograft and lung metastasis models established in 8-week-old male BALB/c nu/nu nude mice. Clinically, FSCN1 and THBS1 are significantly co-overexpressed in ESCC tissues, correlating with advanced disease stages. Notably, hyperacetylation of FSCN1 attenuates its RNA-binding activity, leading to THBS1 mRNA destabilization and consequent suppression of metastatic potential. Our findings reveal a novel RNA-binding function of FSCN1 in posttranscriptional regulation of THBS1, establishing the FSCN1/THBS1/TGF-β axis as a critical driver of ESCC progression. The acetylation-dependent modulation of this pathway highlights the potential therapeutic vulnerability of metastatic ESCC cells.