Targeting the splicing factor SNRPB inhibits endometrial cancer progression by retaining the POLD1 intron

ABSTRACT: Dysregulated alternative splicing has been closely linked to the initiation and progression of tumors. Nevertheless, the precise molecular mechanisms through which splicing factors regulate endometrial cancer progression are still not fully understood. This study demonstrated the elevated expression of the splicing factor SNRPB in endometrial cancer samples. Furthermore, our findings indicated that high levels of SNRPB expression are correlated with a poor prognosis in endometrial cancer patients. Functionally, SNRPB inhibition hindered proliferative and metastatic capacities of endometrial cancer cells. Mechanistically, we revealed that SNRPB knockdown decreased POLD1 expression, and there was retention of POLD1 intron 22 after SNRPB silencing in endometrial cancer cells based on RNA-seq data analysis. The retained intron 22 of POLD1 created a premature termination codon, leading to the absence of amino acids 941 to 1107 and loss of the site of interaction with PCNA, which is essential for POLD1 enzyme activity. In addition, POLD1 depletion decreased the increase in the malignancy of endometrial cancer cells overexpressing SNRPB. Furthermore, miR-654-5p was found to bind to the 3’-UTR of SNRPB directly, resulting in SNRPB expression inhibition in endometrial cancer. Antisense oligonucleotide-mediated SNRPB inhibition led to a decrease in the growth capacity of a CDX model and a PDX model. Overall, SNRPB promotes the efficient splicing of POLD1 by regulating intron retention, ultimately contributing to high POLD1 expression in endometrial cancer. The oncogenic SNRPB/POLD1 axis is an interesting therapeutic target for endometrial cancer, and ASO-mediated silencing of SNRPB may offer a promising therapeutic approach for treating endometrial cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279656 | GEO | 2025/03/12

REPOSITORIES: GEO