SNRPD2-mediated regulation of DDX39B splicing promotes endometrial cancer progression by suppressing the activation of CTSC cryptic exons.

Recent studies have reported the overexpression of Sm proteins in several cancers, suggesting their potential as therapeutic targets; however, the specific Sm family members involved in endometrial cancer and their mechanisms remain unclear. Here, we show that the Sm protein SNRPD2 is markedly upregulated in both fresh-frozen and formalin-fixed paraffin-embedded (FFPE) endometrial cancer specimens and that its overexpression correlates with poorer clinical outcomes. In vitro and in vivo functional assays demonstrate that silencing SNRPD2 suppresses endometrial cancer cell proliferation and metastasis. Specifically, antisense oligonucleotides (ASOs) targeting SNRPD2 markedly reduced tumor growth in a patient-derived xenograft (PDX) model. Mechanistic analyses reveal that SNRPD2 knockdown induces the retention of intron 5 in DDX39B, resulting in the production of a noncoding transcript that is degraded by the nonsense-mediated decay (NMD) pathway and thereby decreases DDX39B expression. Reduced DDX39B levels permit the activation of a cryptic exon (Exon 2_3) in the CTSC mRNA, which introduces premature termination codons (PTCs) and triggers additional NMD-mediated degradation, leading to decreased CTSC expression. Thus, SNRPD2 maintains high DDX39B expression by preventing intron retention, and in turn, elevated DDX39B expression suppresses cryptic exon usage in CTSC to preserve CTSC expression, ultimately supporting malignant phenotypes of endometrial cancer. These results define a novel SNRPD2-DDX39B-CTSC regulatory axis and identify SNRPD2 as a promising therapeutic target for endometrial cancer.