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

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-02-20 DOI:10.1016/j.bbadis.2025.167721

Wei Wei , Yang Zhang , Yibing Li , Jiazhen Huang , Fuli Kang , Shuang Tan , Lin Lin , Xiaohang Lu , Heng Wei , Ning Wang

{"title":"Hypoxia-induced PRPF19 modulates TPT1 alternative splicing to facilitate cisplatin resistance in high-grade serous ovarian cancer","authors":"Wei Wei , Yang Zhang , Yibing Li , Jiazhen Huang , Fuli Kang , Shuang Tan , Lin Lin , Xiaohang Lu , Heng Wei , Ning Wang","doi":"10.1016/j.bbadis.2025.167721","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 4","pages":"Article 167721"},"PeriodicalIF":4.2000,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochimica et biophysica acta. Molecular basis of disease","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0925443925000663","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.