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Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer

Oncogene volume 44, pages 724–738 (2025)Cite this article

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Abstract

Histone lactylation, a novel epigenetic modification, is regulated by the lactate produced by glycolysis. Glycolysis is activated in various cancers, including gastric cancer (GC). However, the molecular mechanism and clinical impact of histone lactylation in GC remain poorly understood. Here, we demonstrate that histone H3K18 lactylation (H3K18la) is elevated in GC, correlating with a worse prognosis. SIRT1 overexpression decreases H3K18la levels, whereas SIRT1 knockdown increases H3K18la levels in GC cells. RNA-seq analysis demonstrates that lncRNA H19 is markedly downregulated in GC cells with SIRT1 overexpression and those grown under glucose free condition, which confirmed decreased H3K18la levels at its promoter region. H19 knockdown decreased the expression levels of LDHA and H3K18la, and LDHA knockdown impaired H19 and H3K18la expression, suggesting an H19/glycolysis/H3K18la-positive feedback loop. Combined treatment with low doses of the SIRT1-specific activator SRT2104 and the LDHA inhibitor oxamate exerted significant antitumor effects on GC cells, with limited adverse effects on normal gastric cells. The SIRT1-weak/H3K18la-strong signature was found to be an independent prognostic factor in patients with GC. Therefore, SIRT1 acts as a histone delactylase for H3K18, and loss of SIRT1 triggers a positive feedback loop involving H19/glycolysis/H3K18la. Targeting this pathway serves as a novel therapeutic strategy for GC treatment.

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Fig. 1: Aberrant levels of global lactylated-lysine (panKla) and H3K18la predict poorer prognosis in patients with gastric cancer.
Fig. 2: SIRT1 acts as a histone delactylase and suppresses cell proliferation and migration.
Fig. 3: Identification of the downregulated genes via histone delactylation in human gastric cancer cell lines.
Fig. 4: H19 promotes aerobic glycolysis and lactylation, upregulating the expression of glycolysis-related genes, including LDHA.
Fig. 5: Dual treatments, inhibition of glycolysis and activation of SIRT1, exhibits a synergistic effect on cell viability.
Fig. 6: The gastric cancer group with weak SIRT1 and strong H19 experiences worse overall survival and recurrence-free survival than other GC groups.

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Data availability

The authors affirm that all data supporting the conclusions of this research are accessible within the article and its Supplementary Information files or can be obtained from the corresponding author upon reasonable request. Our RNA-seq data are registered as GSE276703 and GSE276926.

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Acknowledgements

This study received funding support from Grants-in-Aid for Scientific Research (A, JP19H01055; B, JP23H02979, JP23K27670, JP24K02320), and Challenging Research (Exploratory, 20K21627, and 22K19554) by JSPS KAKENHI; and P-CREATE (JP19cm0106540) and Program for Basic and Clinical Research on Hepatitis (JP24fk0210136, JP24fk0210102, JP24fk0210106, JP24fk0210149) by the Japan Agency for Medical Research and Development (AMED); and Research Grant by the Princess Takamatsu Cancer Research Fund. We also thank Editage (https://www.editage.com) for English language editing and BioRender (https://www.biorender.com) for figure creation. Special thanks go to Ms. Hiromi Onari for her clerical assistance.

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Authors and Affiliations

  1. Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Shu Tsukihara, Yoshimitsu Akiyama, Shu Shimada, Megumi Hatano, Yosuke Igarashi, Tomohiko Taniai, Yoshiaki Tanji, Keita Kodera, Koya Yasukawa, Kentaro Umeura, Atsushi Kamachi, Atsushi Nara & Shinji Tanaka

  2. Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan

    Shu Tsukihara, Yosuke Igarashi, Tomohiko Taniai, Yoshiaki Tanji, Keita Kodera, Toru Ikegami & Ken Eto

  3. Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan

    Koya Yasukawa, Kentaro Umeura & Atsushi Kamachi

  4. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Atsushi Nara & Shinji Tanaka

  5. Department of Gastrointestinal Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Keisuke Okuno, Masanori Tokunaga & Yusuke Kinugasa

  6. Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Hiroto Katoh & Shumpei Ishikawa

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Contributions

STsukihara, YA, and STanaka designed the study and wrote the manuscript. STsukihara, YA, and SS performed the cell biology, histopathology, and bioinformatics analyses. STsukihara, YI, TT, YT, KK, KY, KU, AK, AN and KO contributed to data curation. STsukihara, KO, MT, HK, SI contributed to sample collections. YA, SS, MH, MT, TI, KE, and YK helped write, review, and edit the manuscript. STanaka was responsible for the overall content of this study.

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Correspondence to Yoshimitsu Akiyama or Shinji Tanaka.

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This study was approved by the Ethics Committee of the Faculty of Medicine at Tokyo Medical and Dental University (permission no. M2000-1115-04), and written informed consent was obtained from all patients. Patients were anonymously coded in accordance with the ethical guidelines of the Declaration of Helsinki. The mouse procedures were approved by the Institutional Animal Care and Use Committee of Tokyo Medical and Dental University (permission number 0170135 A).

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Tsukihara, S., Akiyama, Y., Shimada, S. et al. Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer. Oncogene 44, 724–738 (2025). https://doi.org/10.1038/s41388-024-03243-6

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