Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis.

IF 6.1 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2025-02-08 DOI:10.1038/s41420-025-02334-x

Ying Xu, Weiwei Meng, Yingqi Dai, Lin Xu, Ning Ding, Jinqing Zhang, Xuewei Zhuang

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引用次数: 0

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/ )).

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.