Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity
Abstract As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05919-5 |
| _version_ | 1797784386343534592 |
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| author | Yu-Chuan Yan Guang-Xiao Meng Chun-Cheng Yang Ya-Fei Yang Si-Yu Tan Lun-Jie Yan Zi-Niu Ding Yun-Long Ma Zhao-Ru Dong Tao Li |
| author_facet | Yu-Chuan Yan Guang-Xiao Meng Chun-Cheng Yang Ya-Fei Yang Si-Yu Tan Lun-Jie Yan Zi-Niu Ding Yun-Long Ma Zhao-Ru Dong Tao Li |
| author_sort | Yu-Chuan Yan |
| collection | DOAJ |
| description | Abstract As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of components of the DAGLA/2-AG axis in HCC samples is correlated with tumour stage and patient prognosis. In vitro and in vivo experiments demonstrated that the DAGLA/2-AG axis promoted HCC progression by regulating cell proliferation, invasion and metastasis. Mechanistically, the DAGLA/2AG axis significantly inhibited LATS1 and YAP phosphorylation, promoted YAP nuclear translocation and activity, and ultimately led to TEAD2 upregulation and increased PHLDA2 expression, which could be enhanced by DAGLA/2AG-induced activation of the PI3K/AKT pathway. More importantly, DAGLA induced resistance to lenvatinib therapy during HCC treatment. Our study demonstrates that inhibiting the DAGLA/2-AG axis could be a novel therapeutic strategy to inhibit HCC progression and enhance the therapeutic effects of TKIs, which warrant further clinical studies. |
| first_indexed | 2024-03-13T00:39:09Z |
| format | Article |
| id | doaj.art-da00616fe67e4b6aa62f35de36600f6e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-13T00:39:09Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-da00616fe67e4b6aa62f35de36600f6e2023-07-09T11:26:32ZengNature Publishing GroupCell Death and Disease2041-48892023-07-0114711410.1038/s41419-023-05919-5Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activityYu-Chuan Yan0Guang-Xiao Meng1Chun-Cheng Yang2Ya-Fei Yang3Si-Yu Tan4Lun-Jie Yan5Zi-Niu Ding6Yun-Long Ma7Zhao-Ru Dong8Tao Li9Department of General Surgery, Qilu Hospital of Shandong UniversityDepartment of General Surgery, Qilu Hospital of Shandong UniversityDepartment of General Surgery, Qilu Hospital of Shandong UniversityDepartment of General Surgery, Qilu Hospital of Shandong UniversityDepartment of General Surgery, Qilu Hospital of Shandong UniversityDepartment of General Surgery, Qilu Hospital of Shandong UniversityDepartment of General Surgery, Qilu Hospital of Shandong UniversityDepartment of General Surgery, Qilu Hospital of Shandong UniversityDepartment of General Surgery, Qilu Hospital of Shandong UniversityDepartment of General Surgery, Qilu Hospital of Shandong UniversityAbstract As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of components of the DAGLA/2-AG axis in HCC samples is correlated with tumour stage and patient prognosis. In vitro and in vivo experiments demonstrated that the DAGLA/2-AG axis promoted HCC progression by regulating cell proliferation, invasion and metastasis. Mechanistically, the DAGLA/2AG axis significantly inhibited LATS1 and YAP phosphorylation, promoted YAP nuclear translocation and activity, and ultimately led to TEAD2 upregulation and increased PHLDA2 expression, which could be enhanced by DAGLA/2AG-induced activation of the PI3K/AKT pathway. More importantly, DAGLA induced resistance to lenvatinib therapy during HCC treatment. Our study demonstrates that inhibiting the DAGLA/2-AG axis could be a novel therapeutic strategy to inhibit HCC progression and enhance the therapeutic effects of TKIs, which warrant further clinical studies.https://doi.org/10.1038/s41419-023-05919-5 |
| spellingShingle | Yu-Chuan Yan Guang-Xiao Meng Chun-Cheng Yang Ya-Fei Yang Si-Yu Tan Lun-Jie Yan Zi-Niu Ding Yun-Long Ma Zhao-Ru Dong Tao Li Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity Cell Death and Disease |
| title | Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity |
| title_full | Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity |
| title_fullStr | Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity |
| title_full_unstemmed | Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity |
| title_short | Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity |
| title_sort | diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing yap activity |
| url | https://doi.org/10.1038/s41419-023-05919-5 |
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