E3 ligase MG53 suppresses tumor growth by degrading cyclin D1
Abstract Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-07-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-023-01458-9 |
| _version_ | 1797784388146036736 |
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| author | Meng Fang Hong-Kun Wu Yumeng Pei Yan Zhang Xiangyu Gao Yanyun He Gengjia Chen Fengxiang Lv Peng Jiang Yumei Li Wenwen Li Peng Jiang Lin Wang Jiafu Ji Xinli Hu Rui-Ping Xiao |
| author_facet | Meng Fang Hong-Kun Wu Yumeng Pei Yan Zhang Xiangyu Gao Yanyun He Gengjia Chen Fengxiang Lv Peng Jiang Yumei Li Wenwen Li Peng Jiang Lin Wang Jiafu Ji Xinli Hu Rui-Ping Xiao |
| author_sort | Meng Fang |
| collection | DOAJ |
| description | Abstract Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover. |
| first_indexed | 2024-03-13T00:40:10Z |
| format | Article |
| id | doaj.art-e360a05504074936985e799da34289a5 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-03-13T00:40:10Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-e360a05504074936985e799da34289a52023-07-09T11:26:23ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-07-018111210.1038/s41392-023-01458-9E3 ligase MG53 suppresses tumor growth by degrading cyclin D1Meng Fang0Hong-Kun Wu1Yumeng Pei2Yan Zhang3Xiangyu Gao4Yanyun He5Gengjia Chen6Fengxiang Lv7Peng Jiang8Yumei Li9Wenwen Li10Peng Jiang11Lin Wang12Jiafu Ji13Xinli Hu14Rui-Ping Xiao15State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityDepartment of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of MedicineState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Tumor Center, Peking University Cancer Hospital & InstituteState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversitySchool of Life Sciences, Tsinghua UniversityResearch Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Tumor Center, Peking University Cancer Hospital & InstituteState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking UniversityAbstract Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.https://doi.org/10.1038/s41392-023-01458-9 |
| spellingShingle | Meng Fang Hong-Kun Wu Yumeng Pei Yan Zhang Xiangyu Gao Yanyun He Gengjia Chen Fengxiang Lv Peng Jiang Yumei Li Wenwen Li Peng Jiang Lin Wang Jiafu Ji Xinli Hu Rui-Ping Xiao E3 ligase MG53 suppresses tumor growth by degrading cyclin D1 Signal Transduction and Targeted Therapy |
| title | E3 ligase MG53 suppresses tumor growth by degrading cyclin D1 |
| title_full | E3 ligase MG53 suppresses tumor growth by degrading cyclin D1 |
| title_fullStr | E3 ligase MG53 suppresses tumor growth by degrading cyclin D1 |
| title_full_unstemmed | E3 ligase MG53 suppresses tumor growth by degrading cyclin D1 |
| title_short | E3 ligase MG53 suppresses tumor growth by degrading cyclin D1 |
| title_sort | e3 ligase mg53 suppresses tumor growth by degrading cyclin d1 |
| url | https://doi.org/10.1038/s41392-023-01458-9 |
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