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

Abstract

Abstract Ovarian cancer is one of the most prevalent gynecologic malignancies, with a poor prognosis due to its late-stage diagnosis, frequently presenting as highly advanced disease with concomitant drug resistance. Alternative splicing plays an important role in the evolution, development and disease of organisms. Tumor-specific alternative splicing events related to prognosis might be a great significance for tumor diagnosis and prediction and may even become effective targets for tumor therapy. AU-rich element RNA-binding protein 1 (AUF1) is a nucleic acid binding protein that is also known as heterogeneous ribonucleoprotein D (hnRNPD). Alternative splicing of the AUF1 precursor mRNA produces four different mRNA splicing variants, which encode four different molecular weights of protein isoform, p37, p40, p42 and p45 respectively. In this study, we demonstrated that different isoforms of AUF1 played a bidirectional role in ovarian cancer. In ovarian cancer, p37 isoform played a “cancer promoter” role, p42 and p45, especially p45 played a “cancer suppressor” role. The competitive binding of phosphorylated hnRNPA1 and O-GlcNAc modified SRSF2 on exon 2 and exon 7 of AUF1 regulated the alternative splicing of AUF1 and mediated the decrease of cisplatin responsiveness in ovarian cancer. This study provides a new target for exploring the drug resistance mechanism of ovarian cancer.