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. 2024 Dec;47(6):2349-2366.
doi: 10.1007/s13402-024-01023-8. Epub 2024 Dec 9.

Regulation of AUF1 alternative splicing by hnRNPA1 and SRSF2 modulate the sensitivity of ovarian cancer cells to cisplatin

Jia-Mei Wang #  1 , Ning Liu #  2 , Xue-Jing Wei  3 , Fu-Ying Zhao  3 , Chao Li  3 , Hua-Qin Wang  3 , Chuan Liu  4
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Regulation of AUF1 alternative splicing by hnRNPA1 and SRSF2 modulate the sensitivity of ovarian cancer cells to cisplatin

Jia-Mei Wang et al. Cell Oncol (Dordr). 2024 Dec.

Abstract

Purpose: Clarification of cisplatin resistance may provide new targets for therapy in cisplatin resistant ovarian cancer. The current study aims to explore involvement of isoforms of AU-rich element RNA-binding protein 1 (AUF1) in cisplatin resistance in ovarian cancer.

Methods: The cancer stem cell-like features were analyzed using colony formation assay, tumor sphere formation assay and nude mouse xenograft experiments. AUF1 isoforms expression was analyzed using immunoblotting, qRT-PCR, and immunohistochemistry. RIP and Biotin pulldown was used to analyze the interaction of SRSF2 and hnRNPA1 with AUF1 transcript. Transcriptome regulated by AUF1 isoforms was analyzed by RNA-seq.

Results: The current study demonstrated differential expression of AUF1 isoforms in cisplatin sensitive and resistant ovarian cancer tissues and cells. P37 isoform promoted proliferation, while p45 isoform enhanced responsiveness of ovarian cancer cells to cisplatin. the clonal formation capacity of the cells, and the restoration of p45 expression reduced the capacity with cisplatin treatment. The competitive binding of phosphorylated hnRNPA1 and O-GlcNAc-modified SRSF2 on AUF1 exon 2 and exon 7 regulated the alternative splicing of AUF1.

Conclusion: The competitive binding of phosphorylated hnRNPA1 and O-GlcNAc modified SRSF2 on exon 2 and exon 7 regulated the alternative splicing of AUF1 and subsequent isoform expression. P37 isoform played a "cancer promoter" role, p42 and p45, especially p45 played a "cancer suppressor" role in ovarian cancer. This study provides a new target for exploring the drug resistance mechanism of ovarian cancer.

Keywords: AU-rich element RNA-binding protein 1 (AUF1); Alternative splicing; Cisplatin; Ovarian cancer.

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Conflict of interest statement

Declarations. Ethical approval: This study complied with the principles of the Declaration of Helsinki and all procedures for clinical samples were approved by the Institutional Review Committee of The First Hospital of China Medical University (No. [2023] 122). The animal study was approved by the Institutional Review Committee of China Medical University (No. CMUKT2023083). Competing interests: The authors declare no competing interests.

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