Work

Disruption of the SNRPF–DDX24–E2F4 Feedback Loop Uncouples Splicing and Transcriptional Regulation to Suppress Ovarian Cancer Progression

Year: 2026

Type: article

Abstract: Ovarian cancer (OC) remains a major cause of gynecologic cancer mortality, with progress in targeted therapy limited by an incomplete understanding of post-transcriptional oncogenic drivers. Dysregulated RNA splicing-particularly intron retention (IR)-is increasingly recognized as a key driver of tumor progression. Here, integrated transcriptomic and proteomic analyses identify SNRPF, a core spliceosomal component, as a potent oncogenic driver in OC. SNRPF is highly expressed in tumor specimens, and its overexpression predicts poor patient survival. Silencing SNRPF suppresses proliferation, invasion, and xenograft growth. IR-focused analysis reveals that SNRPF depletion induces intron 6 retention in DDX24, disrupting the Helicase_C domain and generating premature termination codons that activate nonsense-mediated decay (NMD), thereby reducing DDX24 protein abundance and markedly impairing its oncogenic function. DDX24 depletion similarly promotes intron 2 retention in E2F4, causing NMD-mediated downregulation. Notably, E2F4 directly binds the SNRPF promoter, forming a self-sustaining "SNRPF-DDX24-E2F4" axis linking splicing and transcriptional regulation. Antisense oligonucleotide-mediated inhibition of SNRPF disrupts this feedback loop, downregulates DDX24 and E2F4 via IR, and significantly impairs tumor growth in vitro, in vivo, and in patient-derived xenografts. These findings define a splicing-transcription coupling mechanism in OC and position SNRPF as a promising therapeutic target.

Source: Advanced Science

DOI: 10.1002/advs.202523374

Authors: Yingwei Li, Zhongshao Chen, Qianqian Gao, Yuehan Gao, Ning Yang

Institutions: Shandong University, Qilu Hospital of Shandong University

Language: English

Topic: RNA Research and Splicing

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $6,730