TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential
Abstract Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-023-00567-7 |
| _version_ | 1797453985823588352 |
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| author | Jing He Mingen Lin Xinchao Zhang Ruonan Zhang Tongguan Tian Yuefan Zhou Wenjing Dong Yajing Yang Xue Sun Yue Dai Yue Xu Zhenru Zhang Ming Xu Qun-Ying Lei Yanping Xu Lei Lv |
| author_facet | Jing He Mingen Lin Xinchao Zhang Ruonan Zhang Tongguan Tian Yuefan Zhou Wenjing Dong Yajing Yang Xue Sun Yue Dai Yue Xu Zhenru Zhang Ming Xu Qun-Ying Lei Yanping Xu Lei Lv |
| author_sort | Jing He |
| collection | DOAJ |
| description | Abstract Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC “eraser” by mRNA oxidation, abolishes YBX1–HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors. |
| first_indexed | 2024-03-09T15:29:45Z |
| format | Article |
| id | doaj.art-f14e9dc959e64d9eb8fb2ae99ea97411 |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-03-09T15:29:45Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-f14e9dc959e64d9eb8fb2ae99ea974112023-11-26T12:19:18ZengNature Publishing GroupCell Discovery2056-59682023-08-019111510.1038/s41421-023-00567-7TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potentialJing He0Mingen Lin1Xinchao Zhang2Ruonan Zhang3Tongguan Tian4Yuefan Zhou5Wenjing Dong6Yajing Yang7Xue Sun8Yue Dai9Yue Xu10Zhenru Zhang11Ming Xu12Qun-Ying Lei13Yanping Xu14Lei Lv15MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityTongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityTongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityUConn Center on Aging, UConn HealthFudan University Shanghai Cancer Center and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityTongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityMOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan UniversityAbstract Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC “eraser” by mRNA oxidation, abolishes YBX1–HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors.https://doi.org/10.1038/s41421-023-00567-7 |
| spellingShingle | Jing He Mingen Lin Xinchao Zhang Ruonan Zhang Tongguan Tian Yuefan Zhou Wenjing Dong Yajing Yang Xue Sun Yue Dai Yue Xu Zhenru Zhang Ming Xu Qun-Ying Lei Yanping Xu Lei Lv TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential Cell Discovery |
| title | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
| title_full | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
| title_fullStr | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
| title_full_unstemmed | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
| title_short | TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential |
| title_sort | tet2 is required to suppress mtorc1 signaling through urea cycle with therapeutic potential |
| url | https://doi.org/10.1038/s41421-023-00567-7 |
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