Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion
Abstract Jagged1 (JAG1) is a Notch ligand that correlates with tumor progression. Not limited to its function as a ligand, JAG1 can be cleaved, and its intracellular domain translocates to the nucleus, where it functions as a transcriptional cofactor. Previously, we showed that JAG1 intracellular do...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06356-0 |
| _version_ | 1797388074346348544 |
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| author | Jung Yun Kim Nayoung Hong Sehyeon Park Seok Won Ham Eun-Jung Kim Sung-Ok Kim Junseok Jang Yoonji Kim Jun-Kyum Kim Sung-Chan Kim Jong-Whi Park Hyunggee Kim |
| author_facet | Jung Yun Kim Nayoung Hong Sehyeon Park Seok Won Ham Eun-Jung Kim Sung-Ok Kim Junseok Jang Yoonji Kim Jun-Kyum Kim Sung-Chan Kim Jong-Whi Park Hyunggee Kim |
| author_sort | Jung Yun Kim |
| collection | DOAJ |
| description | Abstract Jagged1 (JAG1) is a Notch ligand that correlates with tumor progression. Not limited to its function as a ligand, JAG1 can be cleaved, and its intracellular domain translocates to the nucleus, where it functions as a transcriptional cofactor. Previously, we showed that JAG1 intracellular domain (JICD1) forms a protein complex with DDX17/SMAD3/TGIF2. However, the molecular mechanisms underlying JICD1-mediated tumor aggressiveness remains unclear. Here, we demonstrate that JICD1 enhances the invasive phenotypes of glioblastoma cells by transcriptionally activating epithelial-to-mesenchymal transition (EMT)-related genes, especially TWIST1. The inhibition of TWIST1 reduced JICD1-driven tumor aggressiveness. Although SMAD3 is an important component of transforming growth factor (TGF)-β signaling, the JICD1/SMAD3 transcriptional complex was shown to govern brain tumor invasion independent of TGF-β signaling. Moreover, JICD1-TWIST1-MMP2 and MMP9 axes were significantly correlated with clinical outcome of glioblastoma patients. Collectively, we identified the JICD1/SMAD3-TWIST1 axis as a novel inducer of invasive phenotypes in cancer cells. |
| first_indexed | 2024-03-08T22:34:28Z |
| format | Article |
| id | doaj.art-94a6b7e05e354f21b848aee333449959 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-08T22:34:28Z |
| publishDate | 2023-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-94a6b7e05e354f21b848aee3334499592023-12-17T12:31:46ZengNature Publishing GroupCell Death and Disease2041-48892023-12-01141211310.1038/s41419-023-06356-0Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasionJung Yun Kim0Nayoung Hong1Sehyeon Park2Seok Won Ham3Eun-Jung Kim4Sung-Ok Kim5Junseok Jang6Yoonji Kim7Jun-Kyum Kim8Sung-Chan Kim9Jong-Whi Park10Hyunggee Kim11Department of Biotechnology, College of Life Sciences and Biotechnology, Korea UniversityDepartment of Biotechnology, College of Life Sciences and Biotechnology, Korea UniversityDepartment of Biotechnology, College of Life Sciences and Biotechnology, Korea UniversityMEDIFIC Inc.MEDIFIC Inc.Department of Biochemistry, College of Medicine, Hallym UniversityDepartment of Biotechnology, College of Life Sciences and Biotechnology, Korea UniversityDepartment of Biotechnology, College of Life Sciences and Biotechnology, Korea UniversityMEDIFIC Inc.Department of Biochemistry, College of Medicine, Hallym UniversityDepartment of Life Sciences, Gachon UniversityDepartment of Biotechnology, College of Life Sciences and Biotechnology, Korea UniversityAbstract Jagged1 (JAG1) is a Notch ligand that correlates with tumor progression. Not limited to its function as a ligand, JAG1 can be cleaved, and its intracellular domain translocates to the nucleus, where it functions as a transcriptional cofactor. Previously, we showed that JAG1 intracellular domain (JICD1) forms a protein complex with DDX17/SMAD3/TGIF2. However, the molecular mechanisms underlying JICD1-mediated tumor aggressiveness remains unclear. Here, we demonstrate that JICD1 enhances the invasive phenotypes of glioblastoma cells by transcriptionally activating epithelial-to-mesenchymal transition (EMT)-related genes, especially TWIST1. The inhibition of TWIST1 reduced JICD1-driven tumor aggressiveness. Although SMAD3 is an important component of transforming growth factor (TGF)-β signaling, the JICD1/SMAD3 transcriptional complex was shown to govern brain tumor invasion independent of TGF-β signaling. Moreover, JICD1-TWIST1-MMP2 and MMP9 axes were significantly correlated with clinical outcome of glioblastoma patients. Collectively, we identified the JICD1/SMAD3-TWIST1 axis as a novel inducer of invasive phenotypes in cancer cells.https://doi.org/10.1038/s41419-023-06356-0 |
| spellingShingle | Jung Yun Kim Nayoung Hong Sehyeon Park Seok Won Ham Eun-Jung Kim Sung-Ok Kim Junseok Jang Yoonji Kim Jun-Kyum Kim Sung-Chan Kim Jong-Whi Park Hyunggee Kim Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion Cell Death and Disease |
| title | Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion |
| title_full | Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion |
| title_fullStr | Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion |
| title_full_unstemmed | Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion |
| title_short | Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion |
| title_sort | jagged1 intracellular domain smad3 complex transcriptionally regulates twist1 to drive glioma invasion |
| url | https://doi.org/10.1038/s41419-023-06356-0 |
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