METTL3 facilitates renal cell carcinoma progression by PLOD2 m6A-methylation under prolonged hypoxia
Abstract N6-methyladenosine (m6A) is the most prevalent reversible modification in eukaryotic mRNA, and it plays a critical role in tumor progression. The purpose of this study was to investigate the function and regulatory mechanisms of the methyltransferase METTL3 in renal cell carcinoma (RCC). ME...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06411-w |
| _version_ | 1797349625847349248 |
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| author | Yimeng Chen Yichen He Zhengsheng Li Nan Zhang Cuixing Zhou Xiaozhou He Dong Xue |
| author_facet | Yimeng Chen Yichen He Zhengsheng Li Nan Zhang Cuixing Zhou Xiaozhou He Dong Xue |
| author_sort | Yimeng Chen |
| collection | DOAJ |
| description | Abstract N6-methyladenosine (m6A) is the most prevalent reversible modification in eukaryotic mRNA, and it plays a critical role in tumor progression. The purpose of this study was to investigate the function and regulatory mechanisms of the methyltransferase METTL3 in renal cell carcinoma (RCC). METTL3 expression was upregulated and predicted a poor prognosis in patients with advanced RCC. METTL3 facilitated the proliferation, migration, and invasion of RCC cells, depending on its methylase activity. METTL3 positively regulated the expression of PLOD2, and both genes were triggered under prolonged hypoxia. Mechanistically, hypoxia-induced the binding of HIF-1α to the METTL3 promoter, which enhanced its transcriptional activity. METTL3-mediated m6A modifications of PLOD2 mRNA at 3’UTR region, promoting the translation of PLOD2 protein. Furthermore, silencing METTL3 impaired RCC progression in vitro. In vivo, administration of highly potent and selective METTL3 inhibitor STM2457 showed anti-tumor effects, whereas AAV9-mediated re-transduction of PLOD2 largely abolished the above phenomenon in a subcutaneous mouse model. These findings reveal that hypoxia and HIF-driven METTL3 transcription promote RCC progression by increasing PLOD2 expression in an m6A-dependent manner, suggesting that METTL3 may serve as a novel pharmaceutical intervention for RCC. |
| first_indexed | 2024-03-08T12:33:01Z |
| format | Article |
| id | doaj.art-149ecd98a0494e4d9d30c4b5fd0b7ac3 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-08T12:33:01Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-149ecd98a0494e4d9d30c4b5fd0b7ac32024-01-21T12:37:17ZengNature Publishing GroupCell Death and Disease2041-48892024-01-0115111310.1038/s41419-023-06411-wMETTL3 facilitates renal cell carcinoma progression by PLOD2 m6A-methylation under prolonged hypoxiaYimeng Chen0Yichen He1Zhengsheng Li2Nan Zhang3Cuixing Zhou4Xiaozhou He5Dong Xue6Department of Urology, The Third Affiliated Hospital of Soochow UniversityDepartment of Urology, The Third Affiliated Hospital of Soochow UniversityDepartment of Urology, The Third Affiliated Hospital of Soochow UniversityDepartment of Urology, The Third Affiliated Hospital of Soochow UniversityDepartment of Urology, The Third Affiliated Hospital of Soochow UniversityDepartment of Urology, The Third Affiliated Hospital of Soochow UniversityDepartment of Urology, The Third Affiliated Hospital of Soochow UniversityAbstract N6-methyladenosine (m6A) is the most prevalent reversible modification in eukaryotic mRNA, and it plays a critical role in tumor progression. The purpose of this study was to investigate the function and regulatory mechanisms of the methyltransferase METTL3 in renal cell carcinoma (RCC). METTL3 expression was upregulated and predicted a poor prognosis in patients with advanced RCC. METTL3 facilitated the proliferation, migration, and invasion of RCC cells, depending on its methylase activity. METTL3 positively regulated the expression of PLOD2, and both genes were triggered under prolonged hypoxia. Mechanistically, hypoxia-induced the binding of HIF-1α to the METTL3 promoter, which enhanced its transcriptional activity. METTL3-mediated m6A modifications of PLOD2 mRNA at 3’UTR region, promoting the translation of PLOD2 protein. Furthermore, silencing METTL3 impaired RCC progression in vitro. In vivo, administration of highly potent and selective METTL3 inhibitor STM2457 showed anti-tumor effects, whereas AAV9-mediated re-transduction of PLOD2 largely abolished the above phenomenon in a subcutaneous mouse model. These findings reveal that hypoxia and HIF-driven METTL3 transcription promote RCC progression by increasing PLOD2 expression in an m6A-dependent manner, suggesting that METTL3 may serve as a novel pharmaceutical intervention for RCC.https://doi.org/10.1038/s41419-023-06411-w |
| spellingShingle | Yimeng Chen Yichen He Zhengsheng Li Nan Zhang Cuixing Zhou Xiaozhou He Dong Xue METTL3 facilitates renal cell carcinoma progression by PLOD2 m6A-methylation under prolonged hypoxia Cell Death and Disease |
| title | METTL3 facilitates renal cell carcinoma progression by PLOD2 m6A-methylation under prolonged hypoxia |
| title_full | METTL3 facilitates renal cell carcinoma progression by PLOD2 m6A-methylation under prolonged hypoxia |
| title_fullStr | METTL3 facilitates renal cell carcinoma progression by PLOD2 m6A-methylation under prolonged hypoxia |
| title_full_unstemmed | METTL3 facilitates renal cell carcinoma progression by PLOD2 m6A-methylation under prolonged hypoxia |
| title_short | METTL3 facilitates renal cell carcinoma progression by PLOD2 m6A-methylation under prolonged hypoxia |
| title_sort | mettl3 facilitates renal cell carcinoma progression by plod2 m6a methylation under prolonged hypoxia |
| url | https://doi.org/10.1038/s41419-023-06411-w |
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