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 elevated expression of the splicing factor SNRPB in endometrial cancer samples. Furthermore, our findings indicate that high SNRPB expression is correlated with poor prognosis in patients with endometrial cancer. Functionally, SNRPB inhibition hindered the proliferative and metastatic capacities of endometrial cancer cells. Mechanistically, we revealed that SNRPB knockdown decreased POLD1 expression and that POLD1 intron 22 was retained after SNRPB silencing in endometrial cancer cells, as determined via RNA sequencing data analysis. The retained intron 22 of POLD1 created a premature termination codon, leading to the absence of amino acids 941–1,107 and the 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 directly to the 3′ untranslated region of SNRPB, resulting in SNRPB expression inhibition in endometrial cancer. Antisense oligonucleotide-mediated SNRPB inhibition led to a decrease in the growth capacity of a cell-derived xenograft model and a patient with endometrial cancer-derived xenograft 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 antisense oligonucleotide-mediated silencing of SNRPB may constitute a promising therapeutic approach for treating patients with endometrial cancer. Endometrial cancer is a common cancer in women, with rising cases linked to obesity. This study focuses on a protein called SNRPB, which is involved in RNA splicing. SNRPB is found in high levels in endometrial cancer and is linked to poor outcomes. Researchers used various methods, including bioinformatics and lab experiments, to study SNRPB’s role. They found that reducing SNRPB levels slowed cancer cell growth and spread. They also discovered that SNRPB affects another protein, POLD1, which is important for DNA replication and repair. Lowering SNRPB led to changes in POLD1 that hindered cancer progression. This study suggests that targeting SNRPB with antisense oligonucleotides, which are short DNA or RNA molecules designed to block specific genes, could be a promising treatment strategy. This approach could lead to new therapies for endometrial cancer in the future. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.