FAM50A promotes esophageal squamous cell carcinoma progression via splicing-dependent oncogenic circSDK1- and DUSP22-mediated MAPK/FAK activation.

Abstract

Dysregulated splicing factors play critical roles in tumor progression. Here, we identify family with sequence similarity 50 member A (FAM50A) as a pivotal oncogenic splicing factor involved in esophageal squamous cell carcinoma (ESCC). Multi-omics and multi-cohort analyses revealed that FAM50A is upregulated in ESCC and correlates with a poor prognosis. Functional studies demonstrated that FAM50A promotes ESCC proliferation and migration both in vitro and in vivo, primarily through the activation of mitogen-activated protein kinases (MAPKs) and focal adhesion kinase (FAK). We further characterized the FAM50A-binding RNA motif and established its transcriptome-wide splicing landscape. Notably, we identified a novel FAM50A-dependent backsplicing event that generates circSDK1, which originates from exons 2-4 of the sidekick cell adhesion molecule 1 (SDK1) pre-mRNA. Mechanistically, circSDK1 binds to dual-specificity phosphatase 22 (DUSP22) and occupies its phosphatase domain, inhibiting the DUSP22-mediated dephosphorylation of MAPKs and FAK and thereby sustaining their activation. Furthermore, the transcription factor TFAP2C increased FAM50A expression. Finally, we identified rifabutin as a small-molecule inhibitor of FAM50A and confirmed its anti-tumor efficacy in cell-derived xenograft, patient-derived organoid, and patient-derived xenograft models. In summary, FAM50A promotes ESCC progression via the FAM50A/circSDK1/DUSP22 axis, leading to MAPKs and FAK activation. Genetic or pharmacological targeting of FAM50A with rifabutin represents a promising therapeutic strategy for ESCC.