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Article: Therapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer

TitleTherapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer
Authors
Issue Date24-Nov-2023
PublisherAmerican Association for the Advancement of Science
Citation
Science Advances, 2023, v. 9, n. 47 How to Cite?
Abstract

Transcriptional dysregulation is a recurring pathogenic hallmark and an emerging therapeutic vulnerability in ovarian cancer. Here, we demonstrated that ovarian cancer exhibited a unique dependency on the regulatory machinery of transcriptional termination, particularly, cleavage and polyadenylation specificity factor (CPSF) complex. Genetic abrogation of multiple CPSF subunits substantially hampered neoplastic cell viability, and we presented evidence that their indispensable roles converged on the endonuclease CPSF3. Mechanistically, CPSF perturbation resulted in lengthened 3′-untranslated regions, diminished intronic polyadenylation and widespread transcriptional readthrough, and consequently suppressed oncogenic pathways. Furthermore, we reported the development of specific CPSF3 inhibitors building upon the benzoxaborole scaffold, which exerted potent antitumor activity. Notably, CPSF3 blockade effectively exacerbated genomic instability by down-regulating DNA damage repair genes and thus acted in synergy with poly(adenosine 5'-diphosphate–ribose) polymerase inhibition. These findings establish CPSF3-dependent transcriptional termination as an exploitable driving mechanism of ovarian cancer and provide a promising class of boron-containing compounds for targeting transcription-addicted human malignancies.


Persistent Identifierhttp://hdl.handle.net/10722/339903
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorShen, Peiye-
dc.contributor.authorYe, Kaiyan-
dc.contributor.authorXiang, Huaijiang-
dc.contributor.authorZhang, Zhenfeng-
dc.contributor.authorHe, Qinyang-
dc.contributor.authorZhang, Xiao-
dc.contributor.authorCai, Mei-Chun-
dc.contributor.authorChen, Junfei-
dc.contributor.authorSun, Yunheng-
dc.contributor.authorLin, Lifeng-
dc.contributor.authorQi, Chunting-
dc.contributor.authorZhang, Meiying-
dc.contributor.authorCheung, Lydia WT-
dc.contributor.authorShi, Tingyan-
dc.contributor.authorYin, Xia-
dc.contributor.authorLi, Ying-
dc.contributor.authorDi, Wen-
dc.contributor.authorZang, Rongyu-
dc.contributor.authorTan, Li-
dc.contributor.authorZhuang, Guanglei-
dc.date.accessioned2024-03-11T10:40:12Z-
dc.date.available2024-03-11T10:40:12Z-
dc.date.issued2023-11-24-
dc.identifier.citationScience Advances, 2023, v. 9, n. 47-
dc.identifier.urihttp://hdl.handle.net/10722/339903-
dc.description.abstract<p>Transcriptional dysregulation is a recurring pathogenic hallmark and an emerging therapeutic vulnerability in ovarian cancer. Here, we demonstrated that ovarian cancer exhibited a unique dependency on the regulatory machinery of transcriptional termination, particularly, cleavage and polyadenylation specificity factor (CPSF) complex. Genetic abrogation of multiple CPSF subunits substantially hampered neoplastic cell viability, and we presented evidence that their indispensable roles converged on the endonuclease CPSF3. Mechanistically, CPSF perturbation resulted in lengthened 3′-untranslated regions, diminished intronic polyadenylation and widespread transcriptional readthrough, and consequently suppressed oncogenic pathways. Furthermore, we reported the development of specific CPSF3 inhibitors building upon the benzoxaborole scaffold, which exerted potent antitumor activity. Notably, CPSF3 blockade effectively exacerbated genomic instability by down-regulating DNA damage repair genes and thus acted in synergy with poly(adenosine 5'-diphosphate–ribose) polymerase inhibition. These findings establish CPSF3-dependent transcriptional termination as an exploitable driving mechanism of ovarian cancer and provide a promising class of boron-containing compounds for targeting transcription-addicted human malignancies.</p>-
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science-
dc.relation.ispartofScience Advances-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleTherapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer-
dc.typeArticle-
dc.identifier.doi10.1126/sciadv.adj0123-
dc.identifier.scopuseid_2-s2.0-85177827460-
dc.identifier.volume9-
dc.identifier.issue47-
dc.identifier.eissn2375-2548-
dc.identifier.isiWOS:001116509200019-
dc.identifier.issnl2375-2548-

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