Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis
Abstract Histone lactylation plays a crucial role in cancer progression, but its impact on breast cancer (BC) tumorigenesis is still unclear. We utilized chromatin immunoprecipitation sequencing with H3K18la antibodies, transcriptomics of clinical BC samples, and proteomics and ATAC-seq analyses of...
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| Format: | Article |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02334-x |
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| author | Ying Xu Weiwei Meng Yingqi Dai Lin Xu Ning Ding Jinqing Zhang Xuewei Zhuang |
| author_facet | Ying Xu Weiwei Meng Yingqi Dai Lin Xu Ning Ding Jinqing Zhang Xuewei Zhuang |
| author_sort | Ying Xu |
| collection | DOAJ |
| description | Abstract Histone lactylation plays a crucial role in cancer progression, but its impact on breast cancer (BC) tumorigenesis is still unclear. We utilized chromatin immunoprecipitation sequencing with H3K18la antibodies, transcriptomics of clinical BC samples, and proteomics and ATAC-seq analyses of in vivo tumors to identify the genes regulated by H3K18la and the transcription factor PPARD. qPCR and Western blot assays were used to detect expressions of molecules. We discovered that H3K18la levels were higher in BC tissues compared to adjacent non-cancerous tissues. H3K18la promoted the expression of PPARD, which in turn influenced the transcription of AKT, but not ILK. ATAC-seq analysis revealed that glycolysis in BC cells enhanced chromatin accessibility. Additionally, we confirmed that HDAC2 and HDAC3 act as “erasers” for H3 lysine lactylation. During the proteomics analysis, AKT-phosphorylation in the aerobic respiration inhibitor group exhibited an apparent disparity and activity. Our study demonstrated that changes in H3K18la in BC and its downstream transcription factor PPARD support cell survival under anaerobic glycolysis conditions. PPARD accelerated cancer proliferation by promoting the transcription and phosphorylation of AKT. This highlights the therapeutic potential of targeting the H3K18la/PPARD/AKT axis in breast cancer, providing new insights into epigenetic regulation and cancer metabolism (Trial registration: The study was approved by the Research Ethics Committee Shandong Provincial Third Hospital (KYLL-2023057; https://www.medicalresearch.org.cn/ )). |
| format | Article |
| id | doaj-art-d58aeff68fbb48098996bc49139e04ad |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-d58aeff68fbb48098996bc49139e04ad2025-02-09T12:12:28ZengNature Publishing GroupCell Death Discovery2058-77162025-02-0111111610.1038/s41420-025-02334-xAnaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axisYing Xu0Weiwei Meng1Yingqi Dai2Lin Xu3Ning Ding4Jinqing Zhang5Xuewei Zhuang6Department of Thyroid and Breast Surgery, Shandong Provincial Third Hospital, Shandong UniversityDepartment of Clinical Laboratory, Shandong Provincial Third Hospital, Shandong UniversityDepartment of Thyroid and Breast Surgery, Shandong Provincial Third Hospital, Shandong UniversityTranslational Medicine Laboratory, Shandong Provincial Third Hospital, Shandong UniversityDepartment of Anesthesiology, Shandong Provincial Key Medical and Health Laboratory of Intensive Care Rehabilitation, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Thyroid and Breast Surgery, Shandong Provincial Third Hospital, Shandong UniversityDepartment of Clinical Laboratory, Shandong Provincial Third Hospital, Shandong UniversityAbstract Histone lactylation plays a crucial role in cancer progression, but its impact on breast cancer (BC) tumorigenesis is still unclear. We utilized chromatin immunoprecipitation sequencing with H3K18la antibodies, transcriptomics of clinical BC samples, and proteomics and ATAC-seq analyses of in vivo tumors to identify the genes regulated by H3K18la and the transcription factor PPARD. qPCR and Western blot assays were used to detect expressions of molecules. We discovered that H3K18la levels were higher in BC tissues compared to adjacent non-cancerous tissues. H3K18la promoted the expression of PPARD, which in turn influenced the transcription of AKT, but not ILK. ATAC-seq analysis revealed that glycolysis in BC cells enhanced chromatin accessibility. Additionally, we confirmed that HDAC2 and HDAC3 act as “erasers” for H3 lysine lactylation. During the proteomics analysis, AKT-phosphorylation in the aerobic respiration inhibitor group exhibited an apparent disparity and activity. Our study demonstrated that changes in H3K18la in BC and its downstream transcription factor PPARD support cell survival under anaerobic glycolysis conditions. PPARD accelerated cancer proliferation by promoting the transcription and phosphorylation of AKT. This highlights the therapeutic potential of targeting the H3K18la/PPARD/AKT axis in breast cancer, providing new insights into epigenetic regulation and cancer metabolism (Trial registration: The study was approved by the Research Ethics Committee Shandong Provincial Third Hospital (KYLL-2023057; https://www.medicalresearch.org.cn/ )).https://doi.org/10.1038/s41420-025-02334-x |
| spellingShingle | Ying Xu Weiwei Meng Yingqi Dai Lin Xu Ning Ding Jinqing Zhang Xuewei Zhuang Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis Cell Death Discovery |
| title | Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis |
| title_full | Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis |
| title_fullStr | Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis |
| title_full_unstemmed | Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis |
| title_short | Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis |
| title_sort | anaerobic metabolism promotes breast cancer survival via histone 3 lysine 18 lactylation mediating ppard axis |
| url | https://doi.org/10.1038/s41420-025-02334-x |
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