HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1
Abstract Epithelial-mesenchymal transition (EMT) is associated with the invasive and metastatic phenotypes in colorectal cancer (CRC). However, the mechanisms underlying EMT in CRC are not completely understood. In this study, we find that HUNK inhibits EMT and metastasis of CRC cells via its substr...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05849-2 |
| _version_ | 1797822631996555264 |
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| author | Xiaoqi Han Siyuan Jiang Yinmin Gu Lihua Ding Enhao Zhao Dongxing Cao Xiaodong Wang Ya Wen Yongbo Pan Xin Yan Liqiang Duan Minxuan Sun Tao Zhou Yajuan Liu Hongbo Hu Qinong Ye Shan Gao |
| author_facet | Xiaoqi Han Siyuan Jiang Yinmin Gu Lihua Ding Enhao Zhao Dongxing Cao Xiaodong Wang Ya Wen Yongbo Pan Xin Yan Liqiang Duan Minxuan Sun Tao Zhou Yajuan Liu Hongbo Hu Qinong Ye Shan Gao |
| author_sort | Xiaoqi Han |
| collection | DOAJ |
| description | Abstract Epithelial-mesenchymal transition (EMT) is associated with the invasive and metastatic phenotypes in colorectal cancer (CRC). However, the mechanisms underlying EMT in CRC are not completely understood. In this study, we find that HUNK inhibits EMT and metastasis of CRC cells via its substrate GEF-H1 in a kinase-dependent manner. Mechanistically, HUNK directly phosphorylates GEF-H1 at serine 645 (S645) site, which activates RhoA and consequently leads to a cascade of phosphorylation of LIMK-1/CFL-1, thereby stabilizing F-actin and inhibiting EMT. Clinically, the levels of both HUNK expression and phosphorylation S645 of GEH-H1 are not only downregulated in CRC tissues with metastasis compared with that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of HUNK kinase direct phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC. |
| first_indexed | 2024-03-13T10:11:58Z |
| format | Article |
| id | doaj.art-d8c07283e0034b08820e80627d644c12 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-13T10:11:58Z |
| publishDate | 2023-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-d8c07283e0034b08820e80627d644c122023-05-21T11:28:44ZengNature Publishing GroupCell Death and Disease2041-48892023-05-0114511010.1038/s41419-023-05849-2HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1Xiaoqi Han0Siyuan Jiang1Yinmin Gu2Lihua Ding3Enhao Zhao4Dongxing Cao5Xiaodong Wang6Ya Wen7Yongbo Pan8Xin Yan9Liqiang Duan10Minxuan Sun11Tao Zhou12Yajuan Liu13Hongbo Hu14Qinong Ye15Shan Gao16Medical School of Guizhou UniversityZhongda Hospital, Medical School, Advanced Institute for Life and Health, Southeast UniversityZhongda Hospital, Medical School, Advanced Institute for Life and Health, Southeast UniversityDepartment of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer MedicineRenji Hospital, School of Medicine, Shanghai Jiaotong UniversityRenji Hospital, School of Medicine, Shanghai Jiaotong UniversitySuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesMedical School of Guizhou UniversityShanxi Academy of Advanced Research and InnovationShanxi Academy of Advanced Research and InnovationShanxi Academy of Advanced Research and InnovationSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of SciencesShanxi Academy of Advanced Research and InnovationCenter for Immunology and Hematology, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, and Collaborative Innovation Center for BiotherapyDepartment of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer MedicineZhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast UniversityAbstract Epithelial-mesenchymal transition (EMT) is associated with the invasive and metastatic phenotypes in colorectal cancer (CRC). However, the mechanisms underlying EMT in CRC are not completely understood. In this study, we find that HUNK inhibits EMT and metastasis of CRC cells via its substrate GEF-H1 in a kinase-dependent manner. Mechanistically, HUNK directly phosphorylates GEF-H1 at serine 645 (S645) site, which activates RhoA and consequently leads to a cascade of phosphorylation of LIMK-1/CFL-1, thereby stabilizing F-actin and inhibiting EMT. Clinically, the levels of both HUNK expression and phosphorylation S645 of GEH-H1 are not only downregulated in CRC tissues with metastasis compared with that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of HUNK kinase direct phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC.https://doi.org/10.1038/s41419-023-05849-2 |
| spellingShingle | Xiaoqi Han Siyuan Jiang Yinmin Gu Lihua Ding Enhao Zhao Dongxing Cao Xiaodong Wang Ya Wen Yongbo Pan Xin Yan Liqiang Duan Minxuan Sun Tao Zhou Yajuan Liu Hongbo Hu Qinong Ye Shan Gao HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1 Cell Death and Disease |
| title | HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1 |
| title_full | HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1 |
| title_fullStr | HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1 |
| title_full_unstemmed | HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1 |
| title_short | HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1 |
| title_sort | hunk inhibits epithelial mesenchymal transition of crc via direct phosphorylation of gef h1 and activating rhoa limk 1 cfl 1 |
| url | https://doi.org/10.1038/s41419-023-05849-2 |
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