Abstract 297: Targeting splicing factor SF3B4 induces cancer cell senescence by elevating p21 mRNA levels

Abstract SF3B4, a component of U2 snRNP complex, is amplified in various cancers and contributes to cancer cell proliferation, migration and invasion by regulating alternative gene splicing. Despite its potential significance, the mechanisms by which SF3B4 regulates nonsense-mediated mRNA decay (NMD) and cancer cell senescence remain poorly understood. In this study, we reveal a novel regulatory role of SF3B4 in the regulation of cancer cell senescence by targeting p21 mRNA. Depletion of SF3B4 leads to reduced cancer cell proliferation, increased SA-β-Gal positivity, and elevated p21 expression independent of p53, ultimately inducing cellular senescence. Mechanistically, SF3B4 directly binds to the 3’UTR of p21 mRNA, negatively regulating its stability. We demonstrate that SF3B4 plays a crucial role in recruiting key components of the NMD pathway, such as UPF1, MAGOH and RNPS1, to promote the degradation of p21 mRNA. Depletion of SF3B4 disrupted the association of NMD factors from the 3’UTR of p21 mRNA. Taken together, our results reveal a novel regulatory role in which SF3B4 collaborates with NMD factors to regulate p21 mRNA stability and cancer cell senescence. Citation Format: Donghee Kang, Hyun Jung Hwang, Min-Ji Kim, Jae-Seon Lee. Targeting splicing factor SF3B4 induces cancer cell senescence by elevating p21 mRNA levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 297.