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Peer-reviewedCC BY 4.0Advanced Science

Histone Lactylation Drives WNK1 Expression to Promote Esophageal Squamous Cell Carcinoma Progression Through Histone H3 Ser10 Phosphorylation

  • Mingyang Yan1,2
  • Shaobo Fang2,3
  • Yanming Song2
  • Lei Zhang1,2
  • Kexin Zhao1,2
  • Zhenwei Wang1,2
  • Yang Shao4
  • Meng Liu4
  • Xinyang Jia1,2
  • Qinxin Guo1,2
  • Mee‐Hyun Lee1,2
  • Guoguo Jin2,4,5,6,7
1 more authors
  • Zigang Dong1,2,6,7
7 affiliations
  1. 1Department of Pathophysiology School of Basic Medical Sciences Zhengzhou University Zhengzhou Henan China
  2. 2China‐US (Henan) Hormel Cancer Institute Zhengzhou Henan China
  3. 3Department of Radiology Zhengzhou University People's Hospital & Henan Provincial People's Hospital Zhengzhou China
  4. 4Henan Key Laboratory of Chronic Disease Management Fuwai Central China Cardiovascular Hospital Zhengzhou China
  5. 5Central China Subcenter of National Center for Cardiovascular Diseases Henan Cardiovascular Disease Center Fuwai Central‐China Cardiovascular Hospital Central China Fuwai Hospital of Zhengzhou University Zhengzhou China
  6. 6Tianjian Laboratory of Advanced Biomedical Sciences Institute of Advanced Biomedical Sciences Zhengzhou University Zhengzhou Henan China
  7. 7State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer School of Basic Medical Sciences Zhengzhou University Zhengzhou Henan China
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Abstract

Esophageal squamous cell carcinoma (ESCC) lacks effective targeted therapies, and how metabolic reprogramming drives oncogenic signaling remains poorly defined. Here, we identify histone H3 lysine 23 lactylation (H3K23la) as a key epigenetic mediator linking lactate accumulation to tumor progression. H3K23la is upregulated in ESCC and correlates with poor prognosis. Mechanistically, H3K23la promotes WNK lysine deficient protein kinase 1 (WNK1) transcription, which increases histone H3 Ser10 phosphorylation (p‐H3S10) and enhances AKT transcription, thereby driving PI3K‐AKT signaling. This defines a lactate‐H3K23la‐WNK1‐p‐H3S10‐AKT axis connecting metabolism to oncogenic signaling. Importantly, pharmacological inhibition of WNK1 by CD03017 disrupts this pathway and suppresses tumor growth in vitro and in patient‐derived xenograft (PDX) models. In conclusion, our findings define a metabolic‐epigenetic‐signaling axis in ESCC and establish WNK1 as a potential therapeutic target downstream of histone lactylation.

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Cite

BibTeXRIS
BibTeX
@article{yan2026histone,
  title = {{Histone Lactylation Drives WNK1 Expression to Promote Esophageal Squamous Cell Carcinoma Progression Through Histone H3 Ser10 Phosphorylation}},
  author = {Mingyang Yan and Shaobo Fang and Yanming Song and Lei Zhang and Kexin Zhao and Zhenwei Wang and Yang Shao and Meng Liu and Xinyang Jia and Qinxin Guo and Mee‐Hyun Lee and Guoguo Jin and Zigang Dong},
  journal = {Advanced Science},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78438},
  url = {https://doi.org/10.1002/advs.78438},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Histone Lactylation Drives WNK1 Expression to Promote Esophageal Squamous Cell Carcinoma Progression Through Histone H3 Ser10 Phosphorylation
AU  - Mingyang Yan
AU  - Shaobo Fang
AU  - Yanming Song
AU  - Lei Zhang
AU  - Kexin Zhao
AU  - Zhenwei Wang
AU  - Yang Shao
AU  - Meng Liu
AU  - Xinyang Jia
AU  - Qinxin Guo
AU  - Mee‐Hyun Lee
AU  - Guoguo Jin
AU  - Zigang Dong
PY  - 2026
DA  - 2026/10/25
JO  - Advanced Science
DO  - 10.1002/advs.78438
UR  - https://doi.org/10.1002/advs.78438
AB  - Esophageal squamous cell carcinoma (ESCC) lacks effective targeted therapies, and how metabolic reprogramming drives oncogenic signaling remains poorly defined. Here, we identify histone H3 lysine 23 lactylation (H3K23la) as a key epigenetic mediator linking lactate accumulation to tumor progression. H3K23la is upregulated in ESCC and correlates with poor prognosis. Mechanistically, H3K23la promotes WNK lysine deficient protein kinase 1 (WNK1) transcription, which increases histone H3 Ser10 phosphorylation (p‐H3S10) and enhances AKT transcription, thereby driving PI3K‐AKT signaling. This defines a lactate‐H3K23la‐WNK1‐p‐H3S10‐AKT axis connecting metabolism to oncogenic signaling. Importantly, pharmacological inhibition of WNK1 by CD03017 disrupts this pathway and suppresses tumor growth in vitro and in patient‐derived xenograft (PDX) models. In conclusion, our findings define a metabolic‐epigenetic‐signaling axis in ESCC and establish WNK1 as a potential therapeutic target downstream of histone lactylation.
SN  - 2198-3844
ER  -