CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions
Abstract The aberrant upregulation of Yes-associated protein 1 (YAP1) in a variety of solid cancers contributes to tumor progression and poor clinical outcomes, rendering it an appealing therapeutic target. However, effective therapies to directly target YAP1 remain challenging. In this study, we pe...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07323-z |
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| author | Lei Huang Yalei Wen Qin Guo Caishi Zhang Xiao Yang Mei Li YiXia Liu Xinying Li Jiaxin Tang Xiaofeng Zhou Qi Qi Haoxing Zhang Tongzheng Liu |
| author_facet | Lei Huang Yalei Wen Qin Guo Caishi Zhang Xiao Yang Mei Li YiXia Liu Xinying Li Jiaxin Tang Xiaofeng Zhou Qi Qi Haoxing Zhang Tongzheng Liu |
| author_sort | Lei Huang |
| collection | DOAJ |
| description | Abstract The aberrant upregulation of Yes-associated protein 1 (YAP1) in a variety of solid cancers contributes to tumor progression and poor clinical outcomes, rendering it an appealing therapeutic target. However, effective therapies to directly target YAP1 remain challenging. In this study, we perform a high-throughput screening and identify Casein kinase II (CK2) as an uncharacterized upstream regulator of YAP1 turnover in cancer cells of ovarian cancer and several other cancer types. Pharmacological inhibition of Casein kinase II by Silmitasertib or genetic depletion of the catalytic subunit of Casein kinase II (CK2α) markedly destabilizes YAP1 and consequently suppresses its oncogenic functions in vitro and in vivo. Moreover, we reveal that DUB3 as a bona fide deubiquitinase of YAP1, which functionally links CK2 and YAP1 stability in a variety of human cancers. Mechanistically, CK2α directly phosphorylates DUB3 at Thr495, thereby facilitating DUB3-mediated deubiquitination process of YAP1. On the contrary, the loss of Thr495 phosphorylation by the phosphorylation-defective mutant DUB3 T495A, the cancer-related mutant DUB3 D496H and CK2 inhibition failed to deubiquitinate and stabilize YAP1 effectively. Notably, upregulated expressions of CK2α and DUB3 in ovarian cancer positively correlate with YAP1 overexpression. Collectively, our findings demonstrate the functional significance of the CK2α-DUB3 axis in YAP1 stabilization and YAP1-driven tumor progression, highlighting that strategies to target this axis might be of benefit in the clinical management of ovarian cancer and several other lethal cancers with aberrantly upregulated YAP1. |
| format | Article |
| id | doaj-art-24745b52b67b469d820cd9cd532d96c3 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-24745b52b67b469d820cd9cd532d96c32025-01-19T12:40:51ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111410.1038/s41419-024-07323-zCK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functionsLei Huang0Yalei Wen1Qin Guo2Caishi Zhang3Xiao Yang4Mei Li5YiXia Liu6Xinying Li7Jiaxin Tang8Xiaofeng Zhou9Qi Qi10Haoxing Zhang11Tongzheng Liu12Department of General Surgery, Guangzhou Red Cross Hospital/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityResearch Institute for Maternal and Child Health, The Affiliated Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan UniversityDepartment of Pathology, Shanxi Provincial People’s HospitalJianli Traditional Chinese Medicine HospitalDepartment of General Surgery, Guangzhou Red Cross Hospital/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityDepartment of General Surgery, Guangzhou Red Cross Hospital/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityDepartment of General Surgery, Guangzhou Red Cross Hospital/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityDepartment of General Surgery, Guangzhou Red Cross Hospital/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversitySchool of Pharmacology, Lanzhou UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan UniversityGuangdong Provincial Key Laboratory of Genome Stability and Disease Prevention, College of Life Sciences and Oceanography, Shenzhen UniversityDepartment of General Surgery, Guangzhou Red Cross Hospital/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityAbstract The aberrant upregulation of Yes-associated protein 1 (YAP1) in a variety of solid cancers contributes to tumor progression and poor clinical outcomes, rendering it an appealing therapeutic target. However, effective therapies to directly target YAP1 remain challenging. In this study, we perform a high-throughput screening and identify Casein kinase II (CK2) as an uncharacterized upstream regulator of YAP1 turnover in cancer cells of ovarian cancer and several other cancer types. Pharmacological inhibition of Casein kinase II by Silmitasertib or genetic depletion of the catalytic subunit of Casein kinase II (CK2α) markedly destabilizes YAP1 and consequently suppresses its oncogenic functions in vitro and in vivo. Moreover, we reveal that DUB3 as a bona fide deubiquitinase of YAP1, which functionally links CK2 and YAP1 stability in a variety of human cancers. Mechanistically, CK2α directly phosphorylates DUB3 at Thr495, thereby facilitating DUB3-mediated deubiquitination process of YAP1. On the contrary, the loss of Thr495 phosphorylation by the phosphorylation-defective mutant DUB3 T495A, the cancer-related mutant DUB3 D496H and CK2 inhibition failed to deubiquitinate and stabilize YAP1 effectively. Notably, upregulated expressions of CK2α and DUB3 in ovarian cancer positively correlate with YAP1 overexpression. Collectively, our findings demonstrate the functional significance of the CK2α-DUB3 axis in YAP1 stabilization and YAP1-driven tumor progression, highlighting that strategies to target this axis might be of benefit in the clinical management of ovarian cancer and several other lethal cancers with aberrantly upregulated YAP1.https://doi.org/10.1038/s41419-024-07323-z |
| spellingShingle | Lei Huang Yalei Wen Qin Guo Caishi Zhang Xiao Yang Mei Li YiXia Liu Xinying Li Jiaxin Tang Xiaofeng Zhou Qi Qi Haoxing Zhang Tongzheng Liu CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions Cell Death and Disease |
| title | CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions |
| title_full | CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions |
| title_fullStr | CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions |
| title_full_unstemmed | CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions |
| title_short | CK2α-mediated phosphorylation of DUB3 promotes YAP1 stability and oncogenic functions |
| title_sort | ck2α mediated phosphorylation of dub3 promotes yap1 stability and oncogenic functions |
| url | https://doi.org/10.1038/s41419-024-07323-z |
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