PPM1G Inhibits Epithelial–Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter
Abstract Ten–eleven translocation protein 1 (TET1) functions as an epigenetic regulatory molecule, mediating the majority of DNA demethylation, and plays a role in the development of different types of cancers by regulating the expression of proto‐oncogenes and oncogenes. Here it is found that TET1...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407323 |
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| author | Wenzheng Liu Yiyang Kuai Da Wang Junsheng Chen Fei Xiong Guanhua Wu Qi Wang Wenhua Huang Yongqiang Qi Bing Wang Yongjun Chen |
| author_facet | Wenzheng Liu Yiyang Kuai Da Wang Junsheng Chen Fei Xiong Guanhua Wu Qi Wang Wenhua Huang Yongqiang Qi Bing Wang Yongjun Chen |
| author_sort | Wenzheng Liu |
| collection | DOAJ |
| description | Abstract Ten–eleven translocation protein 1 (TET1) functions as an epigenetic regulatory molecule, mediating the majority of DNA demethylation, and plays a role in the development of different types of cancers by regulating the expression of proto‐oncogenes and oncogenes. Here it is found that TET1 is highly expressed in cholangiocarcinoma (CCA) and is associated with a poor prognosis. In addition, TET1 promotes claudin‐3 (CLDN3) transcription by targeting the CLDN3 promoter region between −16 and 512 for demethylation. PPM1G functions as a protein dephosphorylase, catalyzing the dephosphorylation of TET1. This results in the destabilization of the TET1 protein, thereby impairing the targeting of the CLDN3 promoter for demethylation. Two phosphatase inhibitors, staurosporine and AZD0156, inhibit epithelial‐to‐mesenchymal transition (EMT) in cholangiocarcinoma cells by suppressing TET1 expression. In conclusion, it is also demonstrated that PPM1G can be employed as a therapeutic target to impede the progression of CCA by catalyzing the dephosphorylation of TET1, which diminishes the capacity of TET1 to target the CLDN3 promoter to activate transcription and inhibit EMT in CCA. |
| format | Article |
| id | doaj-art-0d3342047f014f5fa1de10d45c4cacd9 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-0d3342047f014f5fa1de10d45c4cacd92025-08-20T01:58:42ZengWileyAdvanced Science2198-38442024-12-011147n/an/a10.1002/advs.202407323PPM1G Inhibits Epithelial–Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 PromoterWenzheng Liu0Yiyang Kuai1Da Wang2Junsheng Chen3Fei Xiong4Guanhua Wu5Qi Wang6Wenhua Huang7Yongqiang Qi8Bing Wang9Yongjun Chen10Department of Biliary‐Pancreatic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaDepartment of General Surgery Beijing Friendship Hospital Capital Medical University Beijing 100050 ChinaDepartment of Biliary‐Pancreatic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaDepartment of Emergency Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430074 ChinaKey Laboratory of Laparoscopic Technology of Zhejiang Province Department of General Surgery Sir Run‐Run Shaw Hospital Zhejiang University School of Medicine Hangzhou 310016 ChinaDepartment of Biliary‐Pancreatic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue Wuhan Hubei 430030 ChinaAbstract Ten–eleven translocation protein 1 (TET1) functions as an epigenetic regulatory molecule, mediating the majority of DNA demethylation, and plays a role in the development of different types of cancers by regulating the expression of proto‐oncogenes and oncogenes. Here it is found that TET1 is highly expressed in cholangiocarcinoma (CCA) and is associated with a poor prognosis. In addition, TET1 promotes claudin‐3 (CLDN3) transcription by targeting the CLDN3 promoter region between −16 and 512 for demethylation. PPM1G functions as a protein dephosphorylase, catalyzing the dephosphorylation of TET1. This results in the destabilization of the TET1 protein, thereby impairing the targeting of the CLDN3 promoter for demethylation. Two phosphatase inhibitors, staurosporine and AZD0156, inhibit epithelial‐to‐mesenchymal transition (EMT) in cholangiocarcinoma cells by suppressing TET1 expression. In conclusion, it is also demonstrated that PPM1G can be employed as a therapeutic target to impede the progression of CCA by catalyzing the dephosphorylation of TET1, which diminishes the capacity of TET1 to target the CLDN3 promoter to activate transcription and inhibit EMT in CCA.https://doi.org/10.1002/advs.202407323cholangiocarcinomademethylationdephosphorylationPPM1GTET1 |
| spellingShingle | Wenzheng Liu Yiyang Kuai Da Wang Junsheng Chen Fei Xiong Guanhua Wu Qi Wang Wenhua Huang Yongqiang Qi Bing Wang Yongjun Chen PPM1G Inhibits Epithelial–Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter Advanced Science cholangiocarcinoma demethylation dephosphorylation PPM1G TET1 |
| title | PPM1G Inhibits Epithelial–Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter |
| title_full | PPM1G Inhibits Epithelial–Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter |
| title_fullStr | PPM1G Inhibits Epithelial–Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter |
| title_full_unstemmed | PPM1G Inhibits Epithelial–Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter |
| title_short | PPM1G Inhibits Epithelial–Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter |
| title_sort | ppm1g inhibits epithelial mesenchymal transition in cholangiocarcinoma by catalyzing tet1 dephosphorylation for destabilization to impair its targeted demethylation of the cldn3 promoter |
| topic | cholangiocarcinoma demethylation dephosphorylation PPM1G TET1 |
| url | https://doi.org/10.1002/advs.202407323 |
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