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  3. H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer

H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer

  • J Exp Clin Cancer Res. 2025 Aug 23;44(1):252. doi: 10.1186/s13046-025-03512-6.
Jiena Liu 1,  Liuying Zhao 1,  Meisi Yan 2,  Shengye Jin 1,  Lingmin Shang 1,  Jianyu Wang 1,  Qin Wang 3 4,  Shilu Zhao 1,  Zibo Shen 5,  Tong Liu 6 7,  Hao Wu 8 9,  Da Pang 10 11 12
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, 150081, China.
  • 2 Department of Pathology, Harbin Medical University, Harbin, Heilongjiang Province, China.
  • 3 Heilongjiang Clinical Research Center for Breast Cancer, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, 150081, China.
  • 4 Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang Province, China.
  • 5 Department of Biomedical and Life Science Faculty, King's College London, London, UK.
  • 6 Department of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, 150081, China. liutong@hrbmu.edu.cn.
  • 7 NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, Heilongjiang Province, China. liutong@hrbmu.edu.cn.
  • 8 Heilongjiang Clinical Research Center for Breast Cancer, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, 150081, China. 3345@hrbmu.edu.cn.
  • 9 Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang Province, China. 3345@hrbmu.edu.cn.
  • 10 Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, 150081, China. pangda@ems.hrbmu.edu.cn.
  • 11 Heilongjiang Clinical Research Center for Breast Cancer, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, 150081, China. pangda@ems.hrbmu.edu.cn.
  • 12 Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang Province, China. pangda@ems.hrbmu.edu.cn.
PMID: 40849487 DOI: 10.1186/s13046-025-03512-6
Abstract

Metabolic reprogramming and epigenetic modification are two hallmarks of Cancer. Protein lysine lactylation (Kla) is a novel type of glycolysis lactate-triggered posttranslational modification. However, the role of Kla in breast Cancer (BC) remains largely unknown. Here, western blot, and immunohistochemical (IHC) staining of BC tissues revealed that global Kla levels were upregulated in BC tissues, and high levels of Kla were correlated with poor prognosis of patients with BC. A series of in vitro and in vivo assays demonstrated that interruption of glycolysis by Lactate Dehydrogenase (LDH) inhibitor or silencing LDHA and LDHB repressed the malignant behaviors of BC cells. Moreover, 4D label-free quantitative lactylproteomics analysis of BC tissues and cells revealed that lactylated proteins widely existed in several subcellular compartments and were closely associated with various cancer-related biological processes. Notably, two previously unresearched sites of histone lactylation, H4K79 lactylation (H4K79la) and H4K91 lactylation (H4K91la), were identified to be hyperlactylated in Cancer tissues and cells. Glycolytic genes, such as Lactate Dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), and Hexokinase 1 (HK1) were identified to be the potential candidate genes epigenetically regulated by H4K79la and H4K91la by intersecting through chromatin immunoprecipitation Sequencing (ChIP-seq), RNA Sequencing (RNA-seq), and TCGA-BRCA database. Pharmacological inhibition of glycolysis downregulated H4K79 and H4K91 lactylation and suppressed the expression of glycolytic genes, whereas treatment with sodium lactate exhibited the opposite effects. Additionally, E1A-binding protein p300 (P300) acted as lysine lactyltransferase to regulate H4K79la and H4K91la, and control the transcription and expression of downstream glycolytic genes in BC cells. The results revealed an intriguing positive feedback loop formed by glycolysis/H4K79la/H4K91la/glycolytic genes in BC, highlighting the relationship between metabolic reprogramming and epigenetic regulation. These findings provide new therapeutic targets for patients with BC.

Keywords

Breast cancer; Epigenetic modification; Glycolysis; Lactylation; Post-translational modifications.

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