IGF2BP3 promotes osteosarcoma malignancy through stabilization of m6A-modified UBE4AmRNA, which involves promotion of NPR3 ubiquitination and degradation

Li, Shuo and Wang, Tianyang and Wang, Erjian and Lin, Lin and Zhong, Wei (2025) IGF2BP3 promotes osteosarcoma malignancy through stabilization of m6A-modified UBE4AmRNA, which involves promotion of NPR3 ubiquitination and degradation. PHYSIOLOGY INTERNATIONAL, 112 (3). pp. 334-350. ISSN 2498-602X

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Abstract

Purpose: Osteosarcoma (OS) is the most common primary bone tumor. Insulin Growth Factor-2 Binding Protein 3 (IGF2BP3) regulates mRNA stability and is a potential oncogene in many cancers, but its role in OS remains unknown. Methods: The CCK-8 assay was used to evaluate the cell viability. Cell cycle and apoptosis were determined using flow cytometry. Real-time PCR and western blot were performed to measure gene expression. Results: Silencing IGF2BP3 weakened cell proliferation and inhibited cell cycle progression. Mechanistically, we demonstrated the regulation of E3 ubiquitin ligase ubiquitination factor E4A (UBE4A) by IGF2BP3. The RIP, MeRIP, and RNA decay assays showed that IGF2BP3 bound to the m6A-modified UBE4A mRNA, thereby enhancing its stability and subsequently promoting the malignant proliferation of OS. Overexpression of UBE4A reversed the decrease in cell viability and induction of apoptosis caused by IGFBP3 knockdown. Furthermore, UBE4A promoted the ubiquitination modification of Natriuretic Peptide Receptor 3 (NPR3), a previously known tumor suppressor in OS. High expression of NPR3 significantly inhibited proliferation and promoted apoptosis in UBE4A-overexpressing cells.Conclusions: IGF2BP3 is upregulated in OS and promotes the malignant phenotype of OS cells. Mechanistically, IGF2BP3 stabilizes UBE4A mRNA to increase UBE4A expression, thereby facilitating the ubiquitination and proteasomal degradation of tumor-suppressor NPR3 to exert pro-tumor functions in OS.

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