RBM39 silence suppresses esophageal cancer proliferation and metastasis via FANCD2 mRNA destabilization.

Abstract

Esophageal cancer (ESCA) is a lethal malignancy with limited therapeutic options and poor survival outcomes. Here, we identify RBM39 as a novel oncoprotein that drives ESCA progression through post-transcriptional stabilization of Fanconi anemia, complementation group D2 (FANCD2) mRNA. RNA-binding motif protein 39 (RBM39) is significantly upregulated in ESCA tissues and cell lines, and its high expression correlates with poor overall survival (OS) and disease-free survival (DFS) in clinical cohorts. Functional studies demonstrate that RBM39 knockdown suppresses proliferation, migration, and invasion in ESCA cells (TE-1, TE-12) in vitro and impairs tumor growth and pulmonary metastasis in xenograft models. Mechanistically, RBM39 directly binds the 3' untranslated regions (3'-UTR) of FANCD2 mRNA (validated by RIP-qPCR and motif mutagenesis), extending its half-life (actinomycin D assay). ESCA transcriptomic profiling of TCGA database links RBM39 to the Fanconi anemia DNA repair pathway, with FANCD2 as its top target. Critically, FANCD2 overexpression rescues oncogenic phenotypes upon RBM39 silencing, restoring tumorigenesis in vivo. These findings establish the RBM39-FANCD2 axis as a therapeutic vulnerability, where targeting the RBM39-FANCD2 axis may offer a promising therapeutic strategy for the ESCA clinical treatment.