EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction
Abstract Myelomatous bone disease is a complication characterized by lytic bone lesions, reduced bone formation, bone pain, and increased fracture risk. Understanding these underlying mechanisms is crucial for developing effective therapeutic approaches. Here we show the role of enhancer of zeste ho...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56506-5 |
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| _version_ | 1832571499503943680 |
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| author | Rui Liu Zongwei Li Rui Chen Zhihong Fang Zhiqiang Liu Huan Liu |
| author_facet | Rui Liu Zongwei Li Rui Chen Zhihong Fang Zhiqiang Liu Huan Liu |
| author_sort | Rui Liu |
| collection | DOAJ |
| description | Abstract Myelomatous bone disease is a complication characterized by lytic bone lesions, reduced bone formation, bone pain, and increased fracture risk. Understanding these underlying mechanisms is crucial for developing effective therapeutic approaches. Here we show the role of enhancer of zeste homolog 2 (EZH2) in bone lesions induced by myeloma cells. Our research reveals that cytokines produced by myeloma-associated adipocytes activate the expression of EZH2 in myeloma cells. Furthermore, we find that EZH2 forms a transcriptional repression complex with transcription factor AP2α. This complex promotes trimethylation at lysine 27 of histone H3 (H3K27me3) in the promoter region of the tumor suppressor gene EMP1, resulting in transcriptional silencing. EMP1 silencing leads to increased myeloma cell proliferation and the concomitant secretion of osteolytic cytokines that contribute to bone destruction. Importantly, EZH2 inhibitors effectively treat myeloma-induced osteolytic lesions. Thus, targeting EZH2 represents a potential therapeutic strategy for preventing and managing myeloma bone disease. |
| format | Article |
| id | doaj-art-270cb7404535498ca54b949584e594bf |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-270cb7404535498ca54b949584e594bf2025-02-02T12:33:13ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-025-56506-5EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destructionRui Liu0Zongwei Li1Rui Chen2Zhihong Fang3Zhiqiang Liu4Huan Liu5Cancer Research Center, School of Medicine, Xiamen UniversitySchool of Life Sciences, Anhui Medical UniversityCancer Research Center, School of Medicine, Xiamen UniversityDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen UniversityShandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical SciencesCancer Research Center, School of Medicine, Xiamen UniversityAbstract Myelomatous bone disease is a complication characterized by lytic bone lesions, reduced bone formation, bone pain, and increased fracture risk. Understanding these underlying mechanisms is crucial for developing effective therapeutic approaches. Here we show the role of enhancer of zeste homolog 2 (EZH2) in bone lesions induced by myeloma cells. Our research reveals that cytokines produced by myeloma-associated adipocytes activate the expression of EZH2 in myeloma cells. Furthermore, we find that EZH2 forms a transcriptional repression complex with transcription factor AP2α. This complex promotes trimethylation at lysine 27 of histone H3 (H3K27me3) in the promoter region of the tumor suppressor gene EMP1, resulting in transcriptional silencing. EMP1 silencing leads to increased myeloma cell proliferation and the concomitant secretion of osteolytic cytokines that contribute to bone destruction. Importantly, EZH2 inhibitors effectively treat myeloma-induced osteolytic lesions. Thus, targeting EZH2 represents a potential therapeutic strategy for preventing and managing myeloma bone disease.https://doi.org/10.1038/s41467-025-56506-5 |
| spellingShingle | Rui Liu Zongwei Li Rui Chen Zhihong Fang Zhiqiang Liu Huan Liu EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction Nature Communications |
| title | EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction |
| title_full | EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction |
| title_fullStr | EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction |
| title_full_unstemmed | EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction |
| title_short | EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction |
| title_sort | ezh2 serves as a viable therapeutic target for myeloma induced osteolytic bone destruction |
| url | https://doi.org/10.1038/s41467-025-56506-5 |
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