Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche
Abstract Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone me...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59381-2 |
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| author | Chenling Meng Kevin Lin Wei Shi Hongqi Teng Xinhai Wan Anna DeBruine Yin Wang Xin Liang Javier Leo Feiyu Chen Qianlin Gu Jie Zhang Vivien Van Kiersten L. Maldonado Boyi Gan Li Ma Yue Lu Di Zhao |
| author_facet | Chenling Meng Kevin Lin Wei Shi Hongqi Teng Xinhai Wan Anna DeBruine Yin Wang Xin Liang Javier Leo Feiyu Chen Qianlin Gu Jie Zhang Vivien Van Kiersten L. Maldonado Boyi Gan Li Ma Yue Lu Di Zhao |
| author_sort | Chenling Meng |
| collection | DOAJ |
| description | Abstract Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs’ differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits robust anti-metastasis responses in preclinical models. Our study demonstrates epigenetic alterations in cancer cells reprogram metabolism and features of myeloid components, facilitating metastatic outgrowth. It establishes ASH1L as an epigenetic driver priming metastasis and macrophage plasticity in the bone niche, providing a bona fide therapeutic target in metastatic malignancies. |
| format | Article |
| id | doaj-art-e046c7323e32427aa63a71604b974d44 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e046c7323e32427aa63a71604b974d442025-08-20T02:29:26ZengNature PortfolioNature Communications2041-17232025-05-0116112310.1038/s41467-025-59381-2Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone nicheChenling Meng0Kevin Lin1Wei Shi2Hongqi Teng3Xinhai Wan4Anna DeBruine5Yin Wang6Xin Liang7Javier Leo8Feiyu Chen9Qianlin Gu10Jie Zhang11Vivien Van12Kiersten L. Maldonado13Boyi Gan14Li Ma15Yue Lu16Di Zhao17Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Endocrine Neoplasia & Hormonal Disorders, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Imaging Physics, The University of Texas MD Anderson Cancer CenterDepartment of Imaging Physics, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterAbstract Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs’ differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits robust anti-metastasis responses in preclinical models. Our study demonstrates epigenetic alterations in cancer cells reprogram metabolism and features of myeloid components, facilitating metastatic outgrowth. It establishes ASH1L as an epigenetic driver priming metastasis and macrophage plasticity in the bone niche, providing a bona fide therapeutic target in metastatic malignancies.https://doi.org/10.1038/s41467-025-59381-2 |
| spellingShingle | Chenling Meng Kevin Lin Wei Shi Hongqi Teng Xinhai Wan Anna DeBruine Yin Wang Xin Liang Javier Leo Feiyu Chen Qianlin Gu Jie Zhang Vivien Van Kiersten L. Maldonado Boyi Gan Li Ma Yue Lu Di Zhao Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche Nature Communications |
| title | Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche |
| title_full | Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche |
| title_fullStr | Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche |
| title_full_unstemmed | Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche |
| title_short | Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche |
| title_sort | histone methyltransferase ash1l primes metastases and metabolic reprogramming of macrophages in the bone niche |
| url | https://doi.org/10.1038/s41467-025-59381-2 |
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