EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma
Abstract Background Overexpressed EZH2 is oncogenically involved in the pathogenesis of different cancerous contexts including extranodal natural killer/T cell lymphoma (ENKTL). However, the underlying mechanisms of EZH2 upregulation have not been fully clarified and it is still difficult to target...
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-023-01606-6 |
| _version_ | 1797414803618136064 |
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| author | Boheng Li Qidi Zhou Qin Wan Xuan Qiao Shangying Chen Jianbiao Zhou Zhijun Wuxiao Lei Luo Siok-Bian Ng Jieping Li Wee-Joo Chng |
| author_facet | Boheng Li Qidi Zhou Qin Wan Xuan Qiao Shangying Chen Jianbiao Zhou Zhijun Wuxiao Lei Luo Siok-Bian Ng Jieping Li Wee-Joo Chng |
| author_sort | Boheng Li |
| collection | DOAJ |
| description | Abstract Background Overexpressed EZH2 is oncogenically involved in the pathogenesis of different cancerous contexts including extranodal natural killer/T cell lymphoma (ENKTL). However, the underlying mechanisms of EZH2 upregulation have not been fully clarified and it is still difficult to target EZH2 in ENKTL. Results Current study identifies an E3 ligase TRIP12 that triggers K63-linked polyubiquitination of EZH2 in ENKTL and unexpectedly, stabilizes EZH2. As determined by gene expression profiling (GEP), TRIP12 and EZH2 levels correlate with each other in ENKTL patient samples. Aided by quantitative mass spectrometry (MS) and follow-up analysis, we identify K634 as the ubiquitination site of EZH2. Further study confirms that TRIP12-mediated EZH2 K634 ubiquitination enhances the interaction between EZH2 and SUZ12 or CDK1 and increases the level of EZH2 T487 phosphorylation. This study further demonstrates the TRIP12-EZH2 signaling might be regulated by cytoplasmic HSP60. Importantly, the TRIP12-EZH2 axis mediates ENKTL cell migration via accelerating epithelial-mesenchymal transition (EMT). Moreover, our study finds out dexamethasone treatment manipulates TRIP12-EZH2 signaling and may represent a novel therapeutic strategy against ENKTL metastasis. Conclusions Altogether, TRIP12 induces K63-linked site-specific polyubiquitination of EZH2 for stabilization, which promotes ENKTL cell migration and could be targeted by dexamethasone treatment. |
| first_indexed | 2024-03-09T05:39:06Z |
| format | Article |
| id | doaj.art-8a31cc0ef54a4c1c9a923fd4f0e59efc |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-03-09T05:39:06Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-8a31cc0ef54a4c1c9a923fd4f0e59efc2023-12-03T12:26:38ZengBMCClinical Epigenetics1868-70832023-11-0115111610.1186/s13148-023-01606-6EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphomaBoheng Li0Qidi Zhou1Qin Wan2Xuan Qiao3Shangying Chen4Jianbiao Zhou5Zhijun Wuxiao6Lei Luo7Siok-Bian Ng8Jieping Li9Wee-Joo Chng10College of Pharmaceutical Sciences, Southwest UniversityCollege of Pharmaceutical Sciences, Southwest UniversityCollege of Pharmaceutical Sciences, Southwest UniversityCollege of Pharmaceutical Sciences, Southwest UniversityBioinformatics Core, Yong Loo Lin School of Medicine, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeDepartment of Hematology, Lymphoma and Myeloma Center, The First Affiliated Hospital of Hainan Medical UniversityCollege of Pharmaceutical Sciences, Southwest UniversityCancer Science Institute of Singapore, National University of SingaporeDepartment of Hematology Oncology, Chongqing University Cancer HospitalCancer Science Institute of Singapore, National University of SingaporeAbstract Background Overexpressed EZH2 is oncogenically involved in the pathogenesis of different cancerous contexts including extranodal natural killer/T cell lymphoma (ENKTL). However, the underlying mechanisms of EZH2 upregulation have not been fully clarified and it is still difficult to target EZH2 in ENKTL. Results Current study identifies an E3 ligase TRIP12 that triggers K63-linked polyubiquitination of EZH2 in ENKTL and unexpectedly, stabilizes EZH2. As determined by gene expression profiling (GEP), TRIP12 and EZH2 levels correlate with each other in ENKTL patient samples. Aided by quantitative mass spectrometry (MS) and follow-up analysis, we identify K634 as the ubiquitination site of EZH2. Further study confirms that TRIP12-mediated EZH2 K634 ubiquitination enhances the interaction between EZH2 and SUZ12 or CDK1 and increases the level of EZH2 T487 phosphorylation. This study further demonstrates the TRIP12-EZH2 signaling might be regulated by cytoplasmic HSP60. Importantly, the TRIP12-EZH2 axis mediates ENKTL cell migration via accelerating epithelial-mesenchymal transition (EMT). Moreover, our study finds out dexamethasone treatment manipulates TRIP12-EZH2 signaling and may represent a novel therapeutic strategy against ENKTL metastasis. Conclusions Altogether, TRIP12 induces K63-linked site-specific polyubiquitination of EZH2 for stabilization, which promotes ENKTL cell migration and could be targeted by dexamethasone treatment.https://doi.org/10.1186/s13148-023-01606-6Extranodal natural killer/T-cell lymphomaMigrationEZH2TRIP12K63-polyubiquitination |
| spellingShingle | Boheng Li Qidi Zhou Qin Wan Xuan Qiao Shangying Chen Jianbiao Zhou Zhijun Wuxiao Lei Luo Siok-Bian Ng Jieping Li Wee-Joo Chng EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma Clinical Epigenetics Extranodal natural killer/T-cell lymphoma Migration EZH2 TRIP12 K63-polyubiquitination |
| title | EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma |
| title_full | EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma |
| title_fullStr | EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma |
| title_full_unstemmed | EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma |
| title_short | EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma |
| title_sort | ezh2 k63 polyubiquitination affecting migration in extranodal natural killer t cell lymphoma |
| topic | Extranodal natural killer/T-cell lymphoma Migration EZH2 TRIP12 K63-polyubiquitination |
| url | https://doi.org/10.1186/s13148-023-01606-6 |
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