RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme
Abstract Glioblastoma multiforme (GBM) is a highly vascularized malignant cancer of the central nervous system, and the presence of vasculogenic mimicry (VM) severely limits the effectiveness of anti-vascular therapy. In this study, we identified downregulated circHECTD1, which acted as a key VM-sup...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06269-y |
| _version_ | 1797556128287031296 |
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| author | Xuelei Ruan Yunhui Liu Ping Wang Libo Liu Teng Ma Yixue Xue Weiwei Dong Yubo Zhao Tiange E Hongda Lin Di Wang Chunqing Yang Jian Song Jiate Liu Meiqi Deng Ping An Yang Lin Jin Yang Zheng Cui Yaming Cao Xiaobai Liu |
| author_facet | Xuelei Ruan Yunhui Liu Ping Wang Libo Liu Teng Ma Yixue Xue Weiwei Dong Yubo Zhao Tiange E Hongda Lin Di Wang Chunqing Yang Jian Song Jiate Liu Meiqi Deng Ping An Yang Lin Jin Yang Zheng Cui Yaming Cao Xiaobai Liu |
| author_sort | Xuelei Ruan |
| collection | DOAJ |
| description | Abstract Glioblastoma multiforme (GBM) is a highly vascularized malignant cancer of the central nervous system, and the presence of vasculogenic mimicry (VM) severely limits the effectiveness of anti-vascular therapy. In this study, we identified downregulated circHECTD1, which acted as a key VM-suppressed factor in GBM. circHECTD1 elevation significantly inhibited cell proliferation, migration, invasion and tube-like structure formation in GBM. RIP assay was used to demonstrate that the flanking intron sequence of circHECTD1 can be specifically bound by RBMS3, thereby inducing circHECTD1 formation to regulate VM formation in GBM. circHECTD1 was confirmed to possess a strong protein-encoding capacity and the encoded functional peptide 463aa was identified by LC-MS/MS. Both circHECTD1 and 463aa significantly inhibited GBM VM formation in vivo and in vitro. Analysis of the 463aa protein sequence revealed that it contained a ubiquitination-related domain and promoted NR2F1 degradation by regulating the ubiquitination of the NR2F1 at K396. ChIP assay verified that NR2F1 could directly bind to the promoter region of MMP2, MMP9 and VE-cadherin, transcriptionally promoting the expression of VM-related proteins, which in turn enhanced VM formation in GBM. In summary, we clarified a novel pathway for RBMS3-induced circHECTD1 encoding functional peptide 463aa to mediate the ubiquitination of NR2F1, which inhibited VM formation in GBM. This study aimed to reveal new mechanisms of GBM progression in order to provide novel approaches and strategies for the anti-vascular therapy of GBM. The schematic illustration showed the inhibitory effect of circHECTD1-463aa in the VM formation in GBM. |
| first_indexed | 2024-03-10T16:57:22Z |
| format | Article |
| id | doaj.art-eb12f8e03f5949bf95a23380ab38c1ed |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-10T16:57:22Z |
| publishDate | 2023-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-eb12f8e03f5949bf95a23380ab38c1ed2023-11-20T11:05:59ZengNature Publishing GroupCell Death and Disease2041-48892023-11-01141111510.1038/s41419-023-06269-yRBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiformeXuelei Ruan0Yunhui Liu1Ping Wang2Libo Liu3Teng Ma4Yixue Xue5Weiwei Dong6Yubo Zhao7Tiange E8Hongda Lin9Di Wang10Chunqing Yang11Jian Song12Jiate Liu13Meiqi Deng14Ping An15Yang Lin16Jin Yang17Zheng Cui18Yaming Cao19Xiaobai Liu20Department of Neurobiology, School of Life Sciences, China Medical UniversityKey Laboratory of Neuro-oncology in Liaoning ProvinceDepartment of Neurobiology, School of Life Sciences, China Medical UniversityDepartment of Neurobiology, School of Life Sciences, China Medical UniversityDepartment of Neurobiology, School of Life Sciences, China Medical UniversityDepartment of Neurobiology, School of Life Sciences, China Medical UniversityKey Laboratory of Neuro-oncology in Liaoning ProvinceKey Laboratory of Neuro-oncology in Liaoning ProvinceKey Laboratory of Neuro-oncology in Liaoning ProvinceKey Laboratory of Neuro-oncology in Liaoning ProvinceKey Laboratory of Neuro-oncology in Liaoning ProvinceKey Laboratory of Neuro-oncology in Liaoning ProvinceKey Laboratory of Neuro-oncology in Liaoning ProvinceKey Laboratory of Neuro-oncology in Liaoning ProvinceKey Laboratory of Neuro-oncology in Liaoning ProvinceDepartment of Neurobiology, School of Life Sciences, China Medical UniversityDepartment of Neurobiology, School of Life Sciences, China Medical UniversityKey Laboratory of Neuro-oncology in Liaoning ProvinceKey Laboratory of Neuro-oncology in Liaoning ProvinceDepartment of Immunology, College of Basic Medical Sciences, China Medical UniversityKey Laboratory of Neuro-oncology in Liaoning ProvinceAbstract Glioblastoma multiforme (GBM) is a highly vascularized malignant cancer of the central nervous system, and the presence of vasculogenic mimicry (VM) severely limits the effectiveness of anti-vascular therapy. In this study, we identified downregulated circHECTD1, which acted as a key VM-suppressed factor in GBM. circHECTD1 elevation significantly inhibited cell proliferation, migration, invasion and tube-like structure formation in GBM. RIP assay was used to demonstrate that the flanking intron sequence of circHECTD1 can be specifically bound by RBMS3, thereby inducing circHECTD1 formation to regulate VM formation in GBM. circHECTD1 was confirmed to possess a strong protein-encoding capacity and the encoded functional peptide 463aa was identified by LC-MS/MS. Both circHECTD1 and 463aa significantly inhibited GBM VM formation in vivo and in vitro. Analysis of the 463aa protein sequence revealed that it contained a ubiquitination-related domain and promoted NR2F1 degradation by regulating the ubiquitination of the NR2F1 at K396. ChIP assay verified that NR2F1 could directly bind to the promoter region of MMP2, MMP9 and VE-cadherin, transcriptionally promoting the expression of VM-related proteins, which in turn enhanced VM formation in GBM. In summary, we clarified a novel pathway for RBMS3-induced circHECTD1 encoding functional peptide 463aa to mediate the ubiquitination of NR2F1, which inhibited VM formation in GBM. This study aimed to reveal new mechanisms of GBM progression in order to provide novel approaches and strategies for the anti-vascular therapy of GBM. The schematic illustration showed the inhibitory effect of circHECTD1-463aa in the VM formation in GBM.https://doi.org/10.1038/s41419-023-06269-y |
| spellingShingle | Xuelei Ruan Yunhui Liu Ping Wang Libo Liu Teng Ma Yixue Xue Weiwei Dong Yubo Zhao Tiange E Hongda Lin Di Wang Chunqing Yang Jian Song Jiate Liu Meiqi Deng Ping An Yang Lin Jin Yang Zheng Cui Yaming Cao Xiaobai Liu RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme Cell Death and Disease |
| title | RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme |
| title_full | RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme |
| title_fullStr | RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme |
| title_full_unstemmed | RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme |
| title_short | RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme |
| title_sort | rbms3 induced circhectd1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme |
| url | https://doi.org/10.1038/s41419-023-06269-y |
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