Hypoxia-induced PRPF19 modulates TPT1 alternative splicing to facilitate cisplatin resistance in high-grade serous ovarian cancer

Abstract

High-grade Serous Ovarian Cancer (HGSOC) is the most common and lethal subtype of ovarian cancer, and chemoresistance is a significant obstacle to its prognosis. The DNA damage response is one of the important mechanisms contributing to chemoresistance. Pre-mRNA processing factor 19 (PRPF19) is essential in DNA damage repair as it can recruit DNA repair proteins. However, the functional role of PRPF19 in HGSOC, especially in chemoresistance, has not been investigated. Herein, we demonstrated that PRPF19 was highly expressed in HGSOC and was associated with poor prognosis. Knockdown of PRPF19 inhibited HGSOC cell proliferation and tumor growth in vivo. In cisplatin-resistant HGSOC cell lines, we observed that knockdown of PRPF19 enhanced cell sensitivity to cisplatin. Mechanistically, PRPF19 silencing induced DNA damage in HGSOC cells, leading to DNA double-strand breaks and ɣH2AX nuclear lesion formation. In addition, mRNA-seq analysis revealed that overexpression of PRPF19 modulates alternative splicing of TPT1, thereby upregulating its expression. Notably, we found that PRPF19 was upregulated under hypoxia. Further examination revealed that hypoxia-inducible factor (HIF)-1α bound to PRPF19 and upregulated PRPF19 expression. In conclusion, these findings suggest that PRPF19 exerts a tumor-promoting effect in HGSOC and may be a novel target for overcoming chemoresistance.