Loss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladder
Abstract Bladder cancer poses significant clinical challenges due to its high metastatic potential and poor prognosis, especially when it progresses to muscle-invasive stages. Here, we show that the m6A reader YTHDC1 is downregulated in muscle-invasive bladder cancer and is negatively correlated wit...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01377-x |
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| author | Jinyun Xu Jonas Koch Claudia Schmidt Malin Nientiedt Manuel Neuberger Philipp Erben Maurice Stephan Michel Manuel Rodríguez-Paredes Frank Lyko |
| author_facet | Jinyun Xu Jonas Koch Claudia Schmidt Malin Nientiedt Manuel Neuberger Philipp Erben Maurice Stephan Michel Manuel Rodríguez-Paredes Frank Lyko |
| author_sort | Jinyun Xu |
| collection | DOAJ |
| description | Abstract Bladder cancer poses significant clinical challenges due to its high metastatic potential and poor prognosis, especially when it progresses to muscle-invasive stages. Here, we show that the m6A reader YTHDC1 is downregulated in muscle-invasive bladder cancer and is negatively correlated with the expression of epithelial‒mesenchymal transition genes. The functional inhibition or depletion of YTHDC1 increased the migration and invasion of urothelial cells. Integrative analysis of multimodal sequencing datasets provided detailed insights into the molecular mechanisms mediating YTHDC1-dependent phenotypes and identified SMAD6 as a key transcript involved in the invasiveness of urothelial carcinoma of the bladder. Notably, SMAD6 mRNA colocalized less with YTHDC1 in tumoral tissues than in paratumoral tissues, indicating disrupted binding during cancer progression. Our findings establish YTHDC1-dependent m6A reading as a critical epitranscriptomic mechanism regulating bladder cancer invasiveness and provide a paradigm for the epitranscriptomic deregulation of cancer-associated networks. |
| format | Article |
| id | doaj-art-3b5056be6d594f63b513767edbbc45a3 |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-3b5056be6d594f63b513767edbbc45a32025-02-09T12:14:08ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-01-0157111813010.1038/s12276-024-01377-xLoss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladderJinyun Xu0Jonas Koch1Claudia Schmidt2Malin Nientiedt3Manuel Neuberger4Philipp Erben5Maurice Stephan Michel6Manuel Rodríguez-Paredes7Frank Lyko8Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research CenterDivision of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research CenterCore Facility Unit Light Microscopy, German Cancer Research CenterDepartment of Urology and Urosurgery, Medical Faculty Mannheim, University of HeidelbergDepartment of Urology and Urosurgery, Medical Faculty Mannheim, University of HeidelbergDepartment of Urology and Urosurgery, Medical Faculty Mannheim, University of HeidelbergDepartment of Urology and Urosurgery, Medical Faculty Mannheim, University of HeidelbergDivision of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research CenterDivision of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research CenterAbstract Bladder cancer poses significant clinical challenges due to its high metastatic potential and poor prognosis, especially when it progresses to muscle-invasive stages. Here, we show that the m6A reader YTHDC1 is downregulated in muscle-invasive bladder cancer and is negatively correlated with the expression of epithelial‒mesenchymal transition genes. The functional inhibition or depletion of YTHDC1 increased the migration and invasion of urothelial cells. Integrative analysis of multimodal sequencing datasets provided detailed insights into the molecular mechanisms mediating YTHDC1-dependent phenotypes and identified SMAD6 as a key transcript involved in the invasiveness of urothelial carcinoma of the bladder. Notably, SMAD6 mRNA colocalized less with YTHDC1 in tumoral tissues than in paratumoral tissues, indicating disrupted binding during cancer progression. Our findings establish YTHDC1-dependent m6A reading as a critical epitranscriptomic mechanism regulating bladder cancer invasiveness and provide a paradigm for the epitranscriptomic deregulation of cancer-associated networks.https://doi.org/10.1038/s12276-024-01377-x |
| spellingShingle | Jinyun Xu Jonas Koch Claudia Schmidt Malin Nientiedt Manuel Neuberger Philipp Erben Maurice Stephan Michel Manuel Rodríguez-Paredes Frank Lyko Loss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladder Experimental and Molecular Medicine |
| title | Loss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladder |
| title_full | Loss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladder |
| title_fullStr | Loss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladder |
| title_full_unstemmed | Loss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladder |
| title_short | Loss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladder |
| title_sort | loss of ythdc1 m6a reading function promotes invasiveness in urothelial carcinoma of the bladder |
| url | https://doi.org/10.1038/s12276-024-01377-x |
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