Tsukihara Shu, Akiyama Yoshimitsu, Shimada Shu, Hatano Megumi, Igarashi Yosuke, Taniai Tomohiko, Tanji Yoshiaki, Kodera Keita, Yasukawa Koya, Umeura Kentaro, Kamachi Atsushi, Nara Atsushi, Okuno Keisuke, Tokunaga Masanori, Katoh Hiroto, Ishikawa Shumpei, Ikegami Toru, Kinugasa Yusuke, Eto Ken, Tanaka Shinji
Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
Oncogene. 2025 Mar;44(11):724-738. doi: 10.1038/s41388-024-03243-6. Epub 2024 Dec 11.
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.
组蛋白乳酸化是一种新型表观遗传修饰，受糖酵解产生的乳酸调控。糖酵解在包括胃癌（GC）在内的多种癌症中被激活。然而，组蛋白乳酸化在胃癌中的分子机制和临床影响仍知之甚少。在此，我们证明组蛋白H3K18乳酸化（H3K18la）在胃癌中升高，与较差的预后相关。SIRT1过表达降低H3K18la水平，而SIRT1敲低则增加胃癌细胞中H3K18la水平。RNA测序分析表明，lncRNA H19在SIRT1过表达的胃癌细胞和无糖培养条件下生长的细胞中显著下调，这证实其启动子区域的H3K18la水平降低。H19敲低降低了LDHA和H3K18la的表达水平，而LDHA敲低则损害了H19和H3K18la的表达，提示存在H19/糖酵解/H3K18la正反馈环。低剂量的SIRT1特异性激活剂SRT2104和LDHA抑制剂草氨酸联合治疗对胃癌细胞具有显著的抗肿瘤作用，对正常胃细胞的不良反应有限。发现SIRT1弱/H3K18la强特征是胃癌患者的独立预后因素。因此，SIRT1作为H3K18的组蛋白去乳酸化酶，SIRT1缺失触发了涉及H19/糖酵解/H3K18la的正反馈环。靶向该途径可作为胃癌治疗的新策略。
