{"title":"Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer.","authors":"Shu Tsukihara, Yoshimitsu Akiyama, Shu Shimada, Megumi Hatano, Yosuke Igarashi, Tomohiko Taniai, Yoshiaki Tanji, Keita Kodera, Koya Yasukawa, Kentaro Umeura, Atsushi Kamachi, Atsushi Nara, Keisuke Okuno, Masanori Tokunaga, Hiroto Katoh, Shumpei Ishikawa, Toru Ikegami, Yusuke Kinugasa, Ken Eto, Shinji Tanaka","doi":"10.1038/s41388-024-03243-6","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9000,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Oncogene","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41388-024-03243-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge.
Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.