Academic Journal
Targeting CPSF73, the mRNA 3' end processing endonuclease, moves cancer cells away from the mesenchymal state.
| Τίτλος: | Targeting CPSF73, the mRNA 3' end processing endonuclease, moves cancer cells away from the mesenchymal state. |
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| Συγγραφείς: | Naseri M; Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States., Liu H; Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States., Wang L; The Wistar Institute, Philadelphia, PA, United States., Mostafa SM; Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States.; Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, United States., Ranaei Pirmardan E; Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States., Tian B; The Wistar Institute, Philadelphia, PA, United States., Moore CL; Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States.; Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, United States. |
| Πηγή: | Frontiers in immunology [Front Immunol] 2026 Aug 05; Vol. 17, pp. 1912261. Date of Electronic Publication: 2026 Aug 05 (Print Publication: 2026). |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| Ιατρικοί όροι (MeSH): | Epithelial-Mesenchymal Transition*/genetics , Epithelial-Mesenchymal Transition*/drug effects , Cleavage And Polyadenylation Specificity Factor*/antagonists & inhibitors , Cleavage And Polyadenylation Specificity Factor*/metabolism , Cleavage And Polyadenylation Specificity Factor*/genetics , Neoplasms*/genetics , Neoplasms*/pathology , Neoplasms*/metabolism , RNA 3' End Processing*, RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Cell Proliferation/drug effects ; Humans ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Polyadenylation ; 3' Untranslated Regions |
| Περίληψη: | Background: Metastasis significantly contributes to cancer-related mortality and therapeutic failure. Cancer cells acquire metastatic potential by losing epithelial characteristics and gaining mesenchymal properties through the epithelial-mesenchymal transition (EMT). Differential poly(A) site (PAS) usage, known as alternative polyadenylation (APA), generates mRNA isoforms differing in coding sequence, subcellular localization, stability, or translation efficiency. In cancer, 3'UTR shortening increases expression of proto-oncogenes by escaping miRNA-mediated repression. High expression of CPSF73, which cleaves mRNA precursors at PASs, is associated with unfavorable prognoses in cancer patients. However, the role of APA in regulating EMT remains poorly understood. Methods: In this study, to investigate the role of APA in EMT, we employed JTE-607, a small-molecule inhibitor of CPSF73 activity, to examine the impact of catalytic inhibition of CPSF73 on proliferation and EMT in MDA-MB-231, MCF7, A549, and HepG2 cancer cells. To identify differential usage of PASs, global profiling of APA changes, and differential gene expression analysis were performed in MDA-MB-231 cells. Additionally, antisense oligonucleotides were used to block the use of a specific PAS whose APA change may be a driver of EMT reversal. Results: Our findings showed that inhibiting the enzymatic activity of CPSF73 both slows cancer cell growth and moves the cells away from the mesenchymal state across all four cell lines tested. Global profiling of APA changes following CPSF73 inhibition revealed widespread 3'UTR lengthening and suppression of intronic PASs in MDA-MB-231 cells. APA shifts were observed in key EMT-related genes, accompanied by decreased expression of corresponding proteins across all four cell lines. We used antisense morpholino oligonucleotides to block the proximal PAS of AKT2, shifting the balance of AKT2 mRNA isoforms toward the long isoform. This shift caused EMT reversal, marked by reduced AKT2 protein expression, changes in EMT-related markers, and impaired invasion by MDA-MB-231 cells. Conclusion: Together, these findings identify APA-mediated 3'UTR lengthening, with functional consequences in EMT-related genes, as a coordinated mechanism leading to an attenuated EMT phenotype, highlighting a significant connection between APA and the EMT process. Interfering with these APA changes may offer a promising therapeutic strategy to suppress metastasis, with potential efficacy across multiple pathways. (Copyright © 2026 Naseri, Liu, Wang, Mostafa, Ranaei Pirmardan, Tian and Moore.) |
| Competing Interests: | The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
| Σχόλια: | Update of: bioRxiv. 2026 Mar 03:2026.03.01.708894. doi: 10.64898/2026.03.01.708894.. (PMID: 41846976) |
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| Grant Information: | R01 AI152337 United States AI NIAID NIH HHS |
| Contributed Indexing: | Keywords: 3′ UTR lengthening; Alternative polyadenylation (APA); CPSF73; Epithelial-mesenchymal transition (EMT); JTE-607 |
| Substance Nomenclature: | 0 (Cleavage And Polyadenylation Specificity Factor) 0 (RNA, Messenger) 0 (3' Untranslated Regions) |
| Entry Date(s): | Date Created: 20260820 Date Completed: 20260820 Latest Revision: 20260828 |
| Update Code: | 20260829 |
| PubMed Central ID: | PMC13485574 |
| DOI: | 10.3389/fimmu.2026.1912261 |
| PMID: | 42620604 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2026.1912261 |