TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma
Abstract Hepatocellular carcinoma (HCC) is a leading cause of global cancer-associated mortality. Although various therapies have substantially ameliorated clinical outcome, patients invariably suffer from cancer relapse, highlighting the need for more optimized therapeutic strategies. Here, we repo...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07745-3 |
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| author | Jing He Mingen Lin Fei Teng Xue Sun Ziyin Tian Jiaxi Li Yan Ma Yue Dai Yi Gao Hongchen Li Tongguan Tian Kai Xu Xinxing Li Lei Lv Yanping Xu |
| author_facet | Jing He Mingen Lin Fei Teng Xue Sun Ziyin Tian Jiaxi Li Yan Ma Yue Dai Yi Gao Hongchen Li Tongguan Tian Kai Xu Xinxing Li Lei Lv Yanping Xu |
| author_sort | Jing He |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is a leading cause of global cancer-associated mortality. Although various therapies have substantially ameliorated clinical outcome, patients invariably suffer from cancer relapse, highlighting the need for more optimized therapeutic strategies. Here, we report that deficiency of DNA methylcytosine dioxygenase TET2 sensitizes HCC cells to sorafenib and verteporfin treatments. Mechanistically, knockout of TET2 enhances the dephosphorylation of YAP Ser127, thus promoting its activity. RNA-seq analysis reveals that MC1R, a GPCR, is strikingly decreased upon TET2 deficiency. Furthermore, TET2 catalyzes demethylation of MC1R promoter to stimulate its transcription. MC1R subsequently boosts cAMP-PKA signaling to phosphorylate YAP Ser127 in both ligand dependent and independent manners. Importantly, deletion of MC1R accelerates tumor growth of HCC, which is reversed by the treatment of YAP-TEAD complex inhibitor verteporfin. Synergistic combination of MC1R expression driver vitamin C and its ligand α-MSH dramatically represses HCC growth. Notably, TET2-MC1R-YAP axis is evidenced in HCC specimens and plays a vital role in prognosis of HCC. Collectively, these findings not only elucidate a previously unidentified epigenetic regulatory mechanism of MC1R transcription and underscore the functional significance of MC1R signaling in tumorigenesis of HCC, but also provide potential targets and clinical strategies for HCC therapy. |
| format | Article |
| id | doaj-art-dc5613464ec0426bbaa9504f7262b511 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-dc5613464ec0426bbaa9504f7262b5112025-08-20T02:05:39ZengNature Publishing GroupCell Death and Disease2041-48892025-06-0116111210.1038/s41419-025-07745-3TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinomaJing He0Mingen Lin1Fei Teng2Xue Sun3Ziyin Tian4Jiaxi Li5Yan Ma6Yue Dai7Yi Gao8Hongchen Li9Tongguan Tian10Kai Xu11Xinxing Li12Lei Lv13Yanping Xu14Tongji 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 UniversityDepartment of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical 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 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 UniversityTongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityDepartment of Gastrointestinal Surgery, Tongji Hospital Medical College of Tongji 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 UniversityAbstract Hepatocellular carcinoma (HCC) is a leading cause of global cancer-associated mortality. Although various therapies have substantially ameliorated clinical outcome, patients invariably suffer from cancer relapse, highlighting the need for more optimized therapeutic strategies. Here, we report that deficiency of DNA methylcytosine dioxygenase TET2 sensitizes HCC cells to sorafenib and verteporfin treatments. Mechanistically, knockout of TET2 enhances the dephosphorylation of YAP Ser127, thus promoting its activity. RNA-seq analysis reveals that MC1R, a GPCR, is strikingly decreased upon TET2 deficiency. Furthermore, TET2 catalyzes demethylation of MC1R promoter to stimulate its transcription. MC1R subsequently boosts cAMP-PKA signaling to phosphorylate YAP Ser127 in both ligand dependent and independent manners. Importantly, deletion of MC1R accelerates tumor growth of HCC, which is reversed by the treatment of YAP-TEAD complex inhibitor verteporfin. Synergistic combination of MC1R expression driver vitamin C and its ligand α-MSH dramatically represses HCC growth. Notably, TET2-MC1R-YAP axis is evidenced in HCC specimens and plays a vital role in prognosis of HCC. Collectively, these findings not only elucidate a previously unidentified epigenetic regulatory mechanism of MC1R transcription and underscore the functional significance of MC1R signaling in tumorigenesis of HCC, but also provide potential targets and clinical strategies for HCC therapy.https://doi.org/10.1038/s41419-025-07745-3 |
| spellingShingle | Jing He Mingen Lin Fei Teng Xue Sun Ziyin Tian Jiaxi Li Yan Ma Yue Dai Yi Gao Hongchen Li Tongguan Tian Kai Xu Xinxing Li Lei Lv Yanping Xu TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma Cell Death and Disease |
| title | TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma |
| title_full | TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma |
| title_fullStr | TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma |
| title_full_unstemmed | TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma |
| title_short | TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma |
| title_sort | tet2 orchestrates yap signaling to potentiate targetable vulnerability in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s41419-025-07745-3 |
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