RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation
Abstract Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for c...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-03-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-024-00654-3 |
| _version_ | 1797247475072892928 |
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| author | Peng Lin Wenyan Chen Zhilin Long Jichuan Yu Jiayao Yang Zhen Xia Qiulian Wu Xinyu Min Jing Tang Ya Cui Fuyi Liu Chun Wang Jian Zheng Wei Li Jeremy N. Rich Lei Li Qi Xie |
| author_facet | Peng Lin Wenyan Chen Zhilin Long Jichuan Yu Jiayao Yang Zhen Xia Qiulian Wu Xinyu Min Jing Tang Ya Cui Fuyi Liu Chun Wang Jian Zheng Wei Li Jeremy N. Rich Lei Li Qi Xie |
| author_sort | Peng Lin |
| collection | DOAJ |
| description | Abstract Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for cancer and other diseases. Here, we performed parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 ligases and deubiquitinases, revealing the E3 ligase RBBP6 as an essential factor for GSC maintenance. Targeting RBBP6 inhibited GSC proliferation and tumor initiation. Mechanistically, RBBP6 mediated K63-linked ubiquitination of Cleavage and Polyadenylation Specific Factor 3 (CPSF3), which stabilized CPSF3 to regulate alternative polyadenylation events. RBBP6 depletion induced shortening of the 3’UTRs of MYC competing-endogenous RNAs to release miR-590-3p from shortened UTRs, thereby decreasing MYC expression. Targeting CPSF3 with a small molecular inhibitor (JTE-607) reduces GSC viability and inhibits in vivo tumor growth. Collectively, RBBP6 maintains high MYC expression in GSCs through regulation of CPSF3-dependent alternative polyadenylation, providing a potential therapeutic paradigm for glioblastoma. |
| first_indexed | 2024-04-24T19:59:17Z |
| format | Article |
| id | doaj.art-7054dc9a7eae487eabc6c694ed88f91a |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-04-24T19:59:17Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-7054dc9a7eae487eabc6c694ed88f91a2024-03-24T12:10:14ZengNature Publishing GroupCell Discovery2056-59682024-03-0110111910.1038/s41421-024-00654-3RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylationPeng Lin0Wenyan Chen1Zhilin Long2Jichuan Yu3Jiayao Yang4Zhen Xia5Qiulian Wu6Xinyu Min7Jing Tang8Ya Cui9Fuyi Liu10Chun Wang11Jian Zheng12Wei Li13Jeremy N. Rich14Lei Li15Qi Xie16College of Life Sciences, Zhejiang UniversityShenzhen Bay LaboratoryWestlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and BiomedicineWestlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and BiomedicineWestlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and BiomedicineWestlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and BiomedicineUniversity of Pittsburgh Medical Center Hillman Cancer Center, Department of Neurology, University of PittsburghWestlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and BiomedicineKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake UniversityDivision of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, IrvineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDivision of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, IrvineUniversity of Pittsburgh Medical Center Hillman Cancer Center, Department of Neurology, University of PittsburghShenzhen Bay LaboratoryWestlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and BiomedicineAbstract Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for cancer and other diseases. Here, we performed parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 ligases and deubiquitinases, revealing the E3 ligase RBBP6 as an essential factor for GSC maintenance. Targeting RBBP6 inhibited GSC proliferation and tumor initiation. Mechanistically, RBBP6 mediated K63-linked ubiquitination of Cleavage and Polyadenylation Specific Factor 3 (CPSF3), which stabilized CPSF3 to regulate alternative polyadenylation events. RBBP6 depletion induced shortening of the 3’UTRs of MYC competing-endogenous RNAs to release miR-590-3p from shortened UTRs, thereby decreasing MYC expression. Targeting CPSF3 with a small molecular inhibitor (JTE-607) reduces GSC viability and inhibits in vivo tumor growth. Collectively, RBBP6 maintains high MYC expression in GSCs through regulation of CPSF3-dependent alternative polyadenylation, providing a potential therapeutic paradigm for glioblastoma.https://doi.org/10.1038/s41421-024-00654-3 |
| spellingShingle | Peng Lin Wenyan Chen Zhilin Long Jichuan Yu Jiayao Yang Zhen Xia Qiulian Wu Xinyu Min Jing Tang Ya Cui Fuyi Liu Chun Wang Jian Zheng Wei Li Jeremy N. Rich Lei Li Qi Xie RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation Cell Discovery |
| title | RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation |
| title_full | RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation |
| title_fullStr | RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation |
| title_full_unstemmed | RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation |
| title_short | RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation |
| title_sort | rbbp6 maintains glioblastoma stem cells through cpsf3 dependent alternative polyadenylation |
| url | https://doi.org/10.1038/s41421-024-00654-3 |
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