Academic Background and Problem Statement

Gastric Cancer (GC) is one of the most common cancers worldwide, with approximately 1.1 million new cases diagnosed in 2020. Although advancements in early detection, surgical techniques, and oncology have led to a decline in GC mortality, the treatment of advanced or metastatic GC remains a significant challenge. In recent years, cancer metabolic reprogramming has emerged as a new strategy for cancer treatment, particularly the activation of glycolysis in cancer cells. Glycolysis not only provides energy for cancer cells but also influences epigenetic modifications, such as histone lactylation, through the production of lactate. Histone lactylation is a novel epigenetic modification that regulates gene transcription via lactate, but its molecular mechanisms and clinical significance in GC remain poorly understood.

This study aims to explore the role of histone lactylation in GC, particularly the relationship between histone H3K18 lactylation (H3K18la) and GC prognosis, and to reveal the delactylase function of SIRT1 (a deacetylase) in histone lactylation. Additionally, the study identifies a positive feedback loop involving long non-coding RNA H19 (lncRNA H19), glycolysis, and histone lactylation, and proposes a novel therapeutic strategy targeting this loop.

Source of the Paper

This paper was authored by Shu Tsukihara, Yoshimitsu Akiyama, and colleagues from Tokyo Medical and Dental University and published in 2024 in the journal Oncogene. The DOI for the paper is https://doi.org/10.1038/s41388-024-03243-6.

Research Process and Results

1. Relationship Between Histone Lactylation and GC Prognosis

The study first analyzed histone lactylation levels in 101 GC tissue samples using immunohistochemistry (IHC). The results showed that histone lactylation levels in GC tissues were significantly higher than in normal gastric tissues, particularly H3K18la levels, which were closely associated with malignant phenotypes such as tumor size and lymph node metastasis. Patients with high H3K18la levels had significantly worse overall survival (OS) and recurrence-free survival (RFS) compared to those with low H3K18la levels, indicating that H3K18la could serve as an independent prognostic marker for GC.

2. SIRT1 as a Histone Delactylase

The study further investigated the role of SIRT1 in histone lactylation. Through in vitro experiments, the research team found that SIRT1 overexpression significantly reduced H3K18la levels in GC cells, while SIRT1 knockdown increased H3K18la levels. Additionally, a catalytically inactive mutant of SIRT1 (H363Y) failed to reduce H3K18la levels, demonstrating that SIRT1 possesses delactylase activity. The study also found that SIRT1’s delactylase function is dependent on the presence of NAD+, further validating its role as a delactylase.

3. Discovery of the H19/Glycolysis/H3K18la Positive Feedback Loop

Through RNA sequencing (RNA-seq) analysis, the research team found that H19 expression was significantly downregulated under conditions of SIRT1 overexpression or glucose deprivation. H19 knockdown not only reduced the expression of lactate dehydrogenase A (LDHA) but also decreased H3K18la levels. Conversely, LDHA knockdown also suppressed H19 and H3K18la expression, indicating the existence of a positive feedback loop involving H19, glycolysis, and H3K18la. This loop is driven by H19 promoting glycolysis, which generates large amounts of lactate, thereby increasing histone lactylation and further activating H19 expression.

4. Therapeutic Strategy Targeting the H19/Glycolysis/H3K18la Loop

The research team evaluated the combined therapeutic effects of the glycolysis inhibitor Oxamate and the SIRT1 activator SRT2104. The results showed that low-dose Oxamate and SRT2104 combination therapy significantly inhibited the proliferation of GC cells with minimal toxicity to normal gastric cells. This combined strategy effectively reduced H3K18la and H19 expression by inhibiting glycolysis and activating SIRT1, thereby disrupting the positive feedback loop.

Research Conclusions and Significance

This study is the first to reveal SIRT1’s function as a histone delactylase and to identify the critical role of the H19/glycolysis/H3K18la positive feedback loop in GC. High H3K18la levels are closely associated with malignant phenotypes and poor prognosis in GC, while the loss of SIRT1 activates this positive feedback loop, promoting GC progression. The proposed combination therapy (Oxamate and SRT2104) offers a new approach for treating GC, particularly for patients with advanced or refractory disease.

Research Highlights

1. H3K18la as an Independent Prognostic Marker for GC: The study found that H3K18la levels are closely associated with malignant phenotypes and poor prognosis in GC, highlighting its clinical significance.
2. SIRT1’s Delactylase Function: This study is the first to reveal SIRT1’s role as a histone delactylase, expanding its function in epigenetic regulation.
3. H19/Glycolysis/H3K18la Positive Feedback Loop: The discovery of this positive feedback loop provides a new therapeutic target for GC.
4. Combination Therapy Strategy: The low-dose combination of Oxamate and SRT2104 effectively inhibits GC cell proliferation with minimal toxicity to normal cells, offering potential clinical applications.

Research Value

This study not only deepens our understanding of the role of histone lactylation in GC but also provides new strategies for GC treatment. By targeting the H19/glycolysis/H3K18la positive feedback loop, the proposed combination therapy holds promise for improving treatment outcomes, especially for patients resistant to current therapies. Furthermore, the discovery of SIRT1’s delactylase function opens new avenues for research into epigenetic regulation in other cancers.