XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1
Abstract X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear....
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07545-9 |
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| _version_ | 1850065705609723904 |
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| author | Ning Sun Sijia Wang Jianting Liu Peipei Zhang Yixin Chang Hongyan Li Kun Zhao Yijie Liu Mingzhi Huang Yan Hu Zhenni Lin Yongyong Lu Guosong Jiang Wei Chen Chuanshu Huang Honglei Jin |
| author_facet | Ning Sun Sijia Wang Jianting Liu Peipei Zhang Yixin Chang Hongyan Li Kun Zhao Yijie Liu Mingzhi Huang Yan Hu Zhenni Lin Yongyong Lu Guosong Jiang Wei Chen Chuanshu Huang Honglei Jin |
| author_sort | Ning Sun |
| collection | DOAJ |
| description | Abstract X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (m6A) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 as its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced the expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of the MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer. |
| format | Article |
| id | doaj-art-31cb9f4bdede49e9b4479b68ee202e5a |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-31cb9f4bdede49e9b4479b68ee202e5a2025-08-20T02:48:57ZengNature Publishing GroupCell Death and Disease2041-48892025-03-0116111110.1038/s41419-025-07545-9XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1Ning Sun0Sijia Wang1Jianting Liu2Peipei Zhang3Yixin Chang4Hongyan Li5Kun Zhao6Yijie Liu7Mingzhi Huang8Yan Hu9Zhenni Lin10Yongyong Lu11Guosong Jiang12Wei Chen13Chuanshu Huang14Honglei Jin15Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Urology, The First Affiliated Hospital of Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Urology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Urology, The First Affiliated Hospital of Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityAbstract X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (m6A) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 as its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced the expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of the MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer.https://doi.org/10.1038/s41419-025-07545-9 |
| spellingShingle | Ning Sun Sijia Wang Jianting Liu Peipei Zhang Yixin Chang Hongyan Li Kun Zhao Yijie Liu Mingzhi Huang Yan Hu Zhenni Lin Yongyong Lu Guosong Jiang Wei Chen Chuanshu Huang Honglei Jin XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1 Cell Death and Disease |
| title | XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1 |
| title_full | XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1 |
| title_fullStr | XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1 |
| title_full_unstemmed | XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1 |
| title_short | XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1 |
| title_sort | xiap promotes metastasis of bladder cancer cells by ubiquitylating ythdc1 |
| url | https://doi.org/10.1038/s41419-025-07545-9 |
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