{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:47:24Z","timestamp":1793371644736,"version":"4.5.0"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970728"],"award-info":[{"award-number":["31970728"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Helicobacter pylori<\/jats:italic>\n                    (\n                    <jats:italic>H. pylori<\/jats:italic>\n                    ) infection mediates activation of oncogenes and inhibition of tumor suppressor genes through aberrant DNA methylation, which is the predominant risk factor for gastric tumorigenesis. Here, by integrating transcriptome and epigenetic multi-omics analyses of gastric tissues and mouse models, we identified that inhibitor of differentiation 4 (ID4) was downregulated in\n                    <jats:italic>H. pylori<\/jats:italic>\n                    -infected gastric tissues and associated with prognosis of gastric cancer (GC).\n                    <jats:italic>H. pylori<\/jats:italic>\n                    infection remarkably increased the methylation level of the ID4 promoter region in the GC patients and mouse models. ID4 served as a tumor suppressor gene in GC and was required for\n                    <jats:italic>H. pylori<\/jats:italic>\n                    -mediated tumorigenic activities in vitro cellular and in vivo tumor-bearing mouse models. Moreover,\n                    <jats:italic>H. pylori<\/jats:italic>\n                    infection induced DNMT3B upregulation through recruiting KLF5 to its promoter and further promoted ID4 DNA methylation modification. Notably, ID4 formed heterodimers with the basic HLH transcription factors DEC1 to inhibit its transcriptional activity; therefore, downregulation of ID4 promoted SHH\/GLI1 signaling through a DEC1 dependent transcriptional modulation. Collectively, our findings indicate\n                    <jats:italic>H. pylori<\/jats:italic>\n                    infection depends on DNMT3B to induce ID4 DNA methylation and ID4 promoter hypermethylation status is a potential biomarker to identify GC. Loss of ID4 could be a key component of\n                    <jats:italic>H. pylori<\/jats:italic>\n                    -mediated gastric tumorigenesis through dysregulation of DEC1\/SHH\/GLI1 axis, which provides potential therapeutic targets in GC.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08042-9","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T08:29:53Z","timestamp":1759825793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Helicobacter pylori-induced aberrant methylation of ID4 mediated by DNMT3B drives gastric cancer progression via DEC1-SHH signaling pathway"],"prefix":"10.1038","volume":"16","author":[{"given":"Muhua","family":"Luan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenshuai","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaotian","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fubo","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanxin","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0279-8354","authenticated-orcid":false,"given":"Xiaoli","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunshan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0670-1604","authenticated-orcid":false,"given":"Yanfei","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"8042_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209\u201349.","journal-title":"CA Cancer J Clin"},{"key":"8042_CR2","doi-asserted-by":"publisher","first-page":"17911","DOI":"10.18632\/oncotarget.3772","volume":"6","author":"M Soutto","year":"2015","unstructured":"Soutto M, Romero-Gallo J, Krishna U, Piazuelo MB, Washington MK, Belkhiri A, et al. Loss of TFF1 promotes Helicobacter pylori-induced \u03b2-catenin activation and gastric tumorigenesis. Oncotarget. 2015;6:17911\u201322.","journal-title":"Oncotarget"},{"key":"8042_CR3","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1053\/j.gastro.2022.01.046","volume":"162","author":"L Cao","year":"2022","unstructured":"Cao L, Zhu S, Lu H, Soutto M, Bhat N, Chen Z, et al. Helicobacter pylori-induced RASAL2 through activation of nuclear factor-\u03baB promotes gastric tumorigenesis via \u03b2-catenin signaling axis. Gastroenterology. 2022;162:1716\u201331.e17.","journal-title":"Gastroenterology"},{"key":"8042_CR4","unstructured":"Infection with Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum. 1994;61:177\u2013240."},{"key":"8042_CR5","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1007\/s10120-016-0650-0","volume":"20","author":"M Maeda","year":"2017","unstructured":"Maeda M, Moro H, Ushijima T. Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway. Gastric Cancer. 2017;20:8\u201315.","journal-title":"Gastric Cancer"},{"key":"8042_CR6","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1158\/0008-5472.CAN-09-2755","volume":"70","author":"T Niwa","year":"2010","unstructured":"Niwa T, Tsukamoto T, Toyoda T, Mori A, Tanaka H, Maekita T, et al. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 2010;70:1430\u201340.","journal-title":"Cancer Res"},{"key":"8042_CR7","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/0092-8674(90)90214-Y","volume":"61","author":"R Benezra","year":"1990","unstructured":"Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell. 1990;61:49\u201359.","journal-title":"Cell"},{"key":"8042_CR8","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/S0962-8924(03)00147-8","volume":"13","author":"MB Ruzinova","year":"2003","unstructured":"Ruzinova MB, Benezra R. Id proteins in development, cell cycle and cancer. Trends Cell Biol. 2003;13:410\u20138.","journal-title":"Trends Cell Biol"},{"key":"8042_CR9","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s12964-016-0161-y","volume":"15","author":"C Roschger","year":"2017","unstructured":"Roschger C, Cabrele C. The Id-protein family in developmental and cancer-associated pathways. Cell Commun Signal. 2017;15:7.","journal-title":"Cell Commun Signal"},{"key":"8042_CR10","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/S1535-6108(03)00141-7","volume":"3","author":"HA Sikder","year":"2003","unstructured":"Sikder HA, Devlin MK, Dunlap S, Ryu B, Alani RM. Id proteins in cell growth and tumorigenesis. Cancer Cell. 2003;3:525\u201330.","journal-title":"Cancer Cell"},{"key":"8042_CR11","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-8-154","volume":"8","author":"E Noetzel","year":"2008","unstructured":"Noetzel E, Veeck J, Niederacher D, Galm O, Horn F, Hartmann A, et al. Promoter methylation-associated loss of ID4 expression is a marker of tumour recurrence in human breast cancer. BMC Cancer. 2008;8:154.","journal-title":"BMC Cancer"},{"key":"8042_CR12","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/s00345-011-0750-8","volume":"30","author":"A Vinarskaja","year":"2012","unstructured":"Vinarskaja A, Goering W, Ingenwerth M, Schulz WA. ID4 is frequently downregulated and partially hypermethylated in prostate cancer. World J Urol. 2012;30:319\u201325.","journal-title":"World J Urol"},{"key":"8042_CR13","doi-asserted-by":"publisher","first-page":"6946","DOI":"10.1038\/sj.onc.1206799","volume":"22","author":"AS Chan","year":"2003","unstructured":"Chan AS, Tsui WY, Chen X, Chu KM, Chan TL, Chan AS, et al. Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma. Oncogene. 2003;22:6946\u201353.","journal-title":"Oncogene"},{"key":"8042_CR14","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/B978-0-12-380866-0.60002-2","volume":"70","author":"M Kulis","year":"2010","unstructured":"Kulis M, Esteller M. DNA methylation and cancer. Adv Genet. 2010;70:27\u201356.","journal-title":"Adv Genet"},{"key":"8042_CR15","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1016\/j.bbagrm.2010.09.002","volume":"1799","author":"M Szyf","year":"2010","unstructured":"Szyf M. DNA methylation and demethylation probed by small molecules. Biochim Biophys Acta. 2010;1799:750\u20139.","journal-title":"Biochim Biophys Acta"},{"key":"8042_CR16","doi-asserted-by":"publisher","first-page":"239","DOI":"10.2478\/jtim-2021-0049","volume":"9","author":"M Zhu","year":"2021","unstructured":"Zhu M, Ding Q, Lin Z, Chen X, Chen S, Zhu Y. New insights of epigenetics in vascular and cellular senescence. J Transl Int Med. 2021;9:239\u201348.","journal-title":"J Transl Int Med"},{"key":"8042_CR17","doi-asserted-by":"publisher","first-page":"2123","DOI":"10.3390\/cancers12082123","volume":"12","author":"J Zhang","year":"2020","unstructured":"Zhang J, Yang C, Wu C, Cui W, Wang L. DNA methyltransferases in cancer: biology, paradox, aberrations, and targeted therapy. Cancers. 2020;12:2123.","journal-title":"Cancers"},{"key":"8042_CR18","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1159\/000511243","volume":"102","author":"G Usui","year":"2021","unstructured":"Usui G, Matsusaka K, Mano Y, Urabe M, Funata S, Fukayama M, et al. DNA methylation and genetic aberrations in gastric cancer. Digestion. 2021;102:25\u201332.","journal-title":"Digestion"},{"key":"8042_CR19","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.jcmgh.2017.01.004","volume":"3","author":"JL Merchant","year":"2017","unstructured":"Merchant JL, Ding L. Hedgehog signaling links chronic inflammation to gastric cancer precursor lesions. Cell Mol Gastroenterol Hepatol. 2017;3:201\u201310.","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"8042_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18632\/genesandcancer.168","volume":"9","author":"AI Akyala","year":"2018","unstructured":"Akyala AI, Peppelenbosch MP. Gastric cancer and Hedgehog signaling pathway: emerging new paradigms. Genes Cancer. 2018;9:1\u201310.","journal-title":"Genes Cancer"},{"key":"8042_CR21","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1053\/j.gastro.2012.01.029","volume":"142","author":"MA Schumacher","year":"2012","unstructured":"Schumacher MA, Donnelly JM, Engevik AC, Xiao C, Yang L, Kenny S, et al. Gastric Sonic Hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori. Gastroenterology. 2012;142:1150\u20139.e6.","journal-title":"Gastroenterology"},{"key":"8042_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/oncsis.2015.38","volume":"4","author":"X Shi","year":"2015","unstructured":"Shi X, Zhan X, Wu J. A positive feedback loop between Gli1 and tyrosine kinase Hck amplifies Shh signaling activities in medulloblastoma. Oncogenesis. 2015;4:e176.","journal-title":"Oncogenesis"},{"key":"8042_CR23","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.canlet.2013.08.016","volume":"345","author":"F Wang","year":"2014","unstructured":"Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014;345:196\u2013202.","journal-title":"Cancer Lett"},{"key":"8042_CR24","doi-asserted-by":"publisher","first-page":"3916","DOI":"10.3748\/wjg.v20.i14.3916","volume":"20","author":"K Matsusaka","year":"2014","unstructured":"Matsusaka K, Funata S, Fukayama M, Kaneda A. DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus. World J Gastroenterol. 2014;20:3916\u201326.","journal-title":"World J Gastroenterol"},{"key":"8042_CR25","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nrg.2017.80","volume":"19","author":"F Lyko","year":"2018","unstructured":"Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2018;19:81\u201392.","journal-title":"Nat Rev Genet"},{"key":"8042_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10238-017-0467-0","volume":"18","author":"Y Pan","year":"2018","unstructured":"Pan Y, Liu G, Zhou F, Su B, Li Y. DNA methylation profiles in cancer diagnosis and therapeutics. Clin Exp Med. 2018;18:1\u201314.","journal-title":"Clin Exp Med"},{"key":"8042_CR27","doi-asserted-by":"publisher","first-page":"3015","DOI":"10.1158\/1535-7163.MCT-10-0609","volume":"9","author":"D Kuck","year":"2010","unstructured":"Kuck D, Caulfield T, Lyko F, Medina-Franco JL. Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells. Mol Cancer Ther. 2010;9:3015\u201323.","journal-title":"Mol Cancer Ther"},{"key":"8042_CR28","doi-asserted-by":"crossref","unstructured":"Sato T, Issa JJ, Kropf P. DNA hypomethylating drugs in cancer therapy. Cold Spring Harbor Perspect Med. 2017;7:a026948.","DOI":"10.1101\/cshperspect.a026948"},{"key":"8042_CR29","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.pharmthera.2018.02.006","volume":"188","author":"K Agrawal","year":"2018","unstructured":"Agrawal K, Das V, Vyas P, Hajd\u00fach M. Nucleosidic DNA demethylating epigenetic drugs\u2014a comprehensive review from discovery to clinic. Pharmacol Ther. 2018;188:45\u201379.","journal-title":"Pharmacol Ther"},{"key":"8042_CR30","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1073\/pnas.0711183105","volume":"105","author":"N Ohnishi","year":"2008","unstructured":"Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, Matsui A, et al. Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci USA. 2008;105:1003\u20138.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8042_CR31","first-page":"4224","volume":"24","author":"P Chen","year":"2020","unstructured":"Chen P, Qian XK, Zhang YF, Sun XG, Shi XJ, Gao YS. KLF5 promotes proliferation in gastric cancer via regulating p21 and CDK4. Eur Rev Med Pharm Sci. 2020;24:4224\u201331.","journal-title":"Eur Rev Med Pharm Sci"},{"key":"8042_CR32","doi-asserted-by":"publisher","first-page":"e54344","DOI":"10.1371\/journal.pone.0054344","volume":"8","author":"JM Noto","year":"2013","unstructured":"Noto JM, Khizanishvili T, Chaturvedi R, Piazuelo MB, Romero-Gallo J, Delgado AG, et al. Helicobacter pylori promotes the expression of Kr\u00fcppel-like factor 5, a mediator of carcinogenesis, in vitro and in vivo. PloS One. 2013;8:e54344.","journal-title":"PloS One"},{"key":"8042_CR33","doi-asserted-by":"publisher","first-page":"20584","DOI":"10.1073\/pnas.1208651109","volume":"109","author":"Y Fujii","year":"2012","unstructured":"Fujii Y, Yoshihashi K, Suzuki H, Tsutsumi S, Mutoh H, Maeda S, et al. CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5. Proc Natl Acad Sci USA. 2012;109:20584\u20139.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8042_CR34","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1016\/j.ajpath.2020.01.021","volume":"190","author":"JJ Balic","year":"2020","unstructured":"Balic JJ, Saad MI, Dawson R, West AJ, McLeod L, West AC, et al. Constitutive STAT3 serine phosphorylation promotes helicobacter-mediated gastric disease. Am J Pathol. 2020;190:1256\u201370.","journal-title":"Am J Pathol"},{"key":"8042_CR35","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1158\/0008-5472.CAN-08-1191","volume":"69","author":"DM Bronte-Tinkew","year":"2009","unstructured":"Bronte-Tinkew DM, Terebiznik M, Franco A, Ang M, Ahn D, Mimuro H, et al. Helicobacter pylori cytotoxin-associated gene A activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo. Cancer Res. 2009;69:632\u20139.","journal-title":"Cancer Res"},{"key":"8042_CR36","doi-asserted-by":"publisher","first-page":"3740","DOI":"10.1002\/jcb.24248","volume":"113","author":"X Zhang","year":"2012","unstructured":"Zhang X, Yang Y, Zhu R, Bai J, Tian Y, Li X, et al. H. pylori induces the expression of Hath1 in gastric epithelial cells via interleukin-8\/STAT3 phosphorylation while suppressing Hes1. J Cell Biochem. 2012;113:3740\u201351.","journal-title":"J Cell Biochem"},{"key":"8042_CR37","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2022.2120744","volume":"14","author":"D Jin","year":"2022","unstructured":"Jin D, Huang K, Xu M, Hua H, Ye F, Yan J, et al. Deoxycholic acid induces gastric intestinal metaplasia by activating STAT3 signaling and disturbing gastric bile acids metabolism and microbiota. Gut Microbes. 2022;14:2120744.","journal-title":"Gut Microbes"},{"key":"8042_CR38","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s12964-017-0171-4","volume":"15","author":"S Wessler","year":"2017","unstructured":"Wessler S, Krisch LM, Elmer DP, Aberger F. From inflammation to gastric cancer - the importance of Hedgehog\/GLI signaling in Helicobacter pylori-induced chronic inflammatory and neoplastic diseases. Cell Commun Signal. 2017;15:15.","journal-title":"Cell Commun Signal"},{"key":"8042_CR39","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1111\/hel.12152","volume":"20","author":"MA Schumacher","year":"2015","unstructured":"Schumacher MA, Feng R, Aihara E, Engevik AC, Montrose MH, Ottemann KM, et al. Helicobacter pylori-induced Sonic Hedgehog expression is regulated by NF\u03baB pathway activation: the use of a novel in vitro model to study epithelial response to infection. Helicobacter. 2015;20:19\u201328.","journal-title":"Helicobacter"},{"key":"8042_CR40","first-page":"1523","volume":"23","author":"JH Kim","year":"2010","unstructured":"Kim JH, Choi YJ, Lee SH, Shin HS, Lee IO, Kim YJ, et al. Effect of Helicobacter pylori infection on the sonic hedgehog signaling pathway in gastric cancer cells. Oncol Rep. 2010;23:1523\u20138.","journal-title":"Oncol Rep"},{"key":"8042_CR41","doi-asserted-by":"publisher","first-page":"9261","DOI":"10.1002\/jcp.27030","volume":"233","author":"S Fattahi","year":"2018","unstructured":"Fattahi S, Kosari-Monfared M, Ghadami E, Golpour M, Khodadadi P, Ghasemiyan M, et al. Infection-associated epigenetic alterations in gastric cancer: new insight in cancer therapy. J Cell Physiol. 2018;233:9261\u201370.","journal-title":"J Cell Physiol"},{"key":"8042_CR42","doi-asserted-by":"crossref","unstructured":"Muhammad JS, Eladl MA, Khoder G. Helicobacter pylori-induced DNA methylation as an epigenetic modulator of gastric cancer: recent outcomes and future direction. Pathogens. 2019;8:23.","DOI":"10.3390\/pathogens8010023"},{"key":"8042_CR43","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-9-173","volume":"9","author":"JP Carey","year":"2009","unstructured":"Carey JP, Asirvatham AJ, Galm O, Ghogomu TA, Chaudhary J. Inhibitor of differentiation 4 (Id4) is a potential tumor suppressor in prostate cancer. BMC Cancer. 2009;9:173.","journal-title":"BMC Cancer"},{"key":"8042_CR44","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-018-0542-8","volume":"10","author":"D Nasif","year":"2018","unstructured":"Nasif D, Campoy E, Laurito S, Branham R, Urrutia G, Roqu\u00e9 M, et al. Epigenetic regulation of ID4 in breast cancer: tumor suppressor or oncogene?. Clin Epigenet. 2018;10:111.","journal-title":"Clin Epigenet"},{"key":"8042_CR45","first-page":"185","volume":"33","author":"T G\u00f3mez Del Pulgar","year":"2008","unstructured":"G\u00f3mez Del Pulgar T, Vald\u00e9s-Mora F, Bandr\u00e9s E, P\u00e9rez-Palacios R, Espina C, Cejas P, et al. Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism. Int J Oncol. 2008;33:185\u201393.","journal-title":"Int J Oncol"},{"key":"8042_CR46","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-8-86","volume":"8","author":"M Castro","year":"2010","unstructured":"Castro M, Grau L, Puerta P, Gimenez L, Venditti J, Quadrelli S, et al. Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in lung cancer. J Transl Med. 2010;8:86.","journal-title":"J Transl Med"},{"key":"8042_CR47","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1002\/cbf.3126","volume":"33","author":"MM Sarabi","year":"2015","unstructured":"Sarabi MM, Naghibalhossaini F. Association of DNA methyltransferases expression with global and gene-specific DNA methylation in colorectal cancer cells. Cell Biochem Funct. 2015;33:427\u201333.","journal-title":"Cell Biochem Funct"},{"key":"8042_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36019-9","volume":"14","author":"S Andrews","year":"2023","unstructured":"Andrews S, Krueger C, Mellado-Lopez M, Hemberger M, Dean W, Perez-Garcia V, et al. Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B. Nat Commun. 2023;14:371.","journal-title":"Nat Commun"},{"key":"8042_CR49","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.ctrv.2017.01.004","volume":"54","author":"JF Linnekamp","year":"2017","unstructured":"Linnekamp JF, Butter R, Spijker R, Medema JP, van Laarhoven HWM. Clinical and biological effects of demethylating agents on solid tumours\u2014A systematic review. Cancer Treat Rev. 2017;54:10\u201323.","journal-title":"Cancer Treat Rev"},{"key":"8042_CR50","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-019-0709-y","volume":"11","author":"N Hattori","year":"2019","unstructured":"Hattori N, Sako M, Kimura K, Iida N, Takeshima H, Nakata Y, et al. Novel prodrugs of decitabine with greater metabolic stability and less toxicity. Clin Epigenet. 2019;11:111.","journal-title":"Clin Epigenet"},{"key":"8042_CR51","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1084\/jem.191.4.593","volume":"191","author":"M Asahi","year":"2000","unstructured":"Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y, et al. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med. 2000;191:593\u2013602.","journal-title":"J Exp Med"},{"key":"8042_CR52","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2024.2314201","volume":"16","author":"SC Tran","year":"2024","unstructured":"Tran SC, Bryant KN, Cover TL. The Helicobacter pylori cag pathogenicity island as a determinant of gastric cancer risk. Gut Microbes. 2024;16:2314201.","journal-title":"Gut Microbes"},{"key":"8042_CR53","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1136\/gutjnl-2011-301625","volume":"62","author":"Y Hayashi","year":"2013","unstructured":"Hayashi Y, Tsujii M, Wang J, Kondo J, Akasaka T, Jin Y, et al. CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori-related carcinogenesis. Gut. 2013;62:1536\u201346.","journal-title":"Gut"},{"key":"8042_CR54","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/nrc3638","volume":"14","author":"A Lasorella","year":"2014","unstructured":"Lasorella A, Benezra R, Iavarone A. The ID proteins: master regulators of cancer stem cells and tumour aggressiveness. Nat Rev Cancer. 2014;14:77\u201391.","journal-title":"Nat Rev Cancer"},{"key":"8042_CR55","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1136\/annrheumdis-2015-208470","volume":"76","author":"K Palumbo-Zerr","year":"2017","unstructured":"Palumbo-Zerr K, Soare A, Zerr P, Liebl A, Mancuso R, Tomcik M, et al. Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis. Ann Rheum Dis. 2017;76:244\u201351.","journal-title":"Ann Rheum Dis"},{"key":"8042_CR56","doi-asserted-by":"publisher","first-page":"4131","DOI":"10.1242\/dev.01273","volume":"131","author":"J Samanta","year":"2004","unstructured":"Samanta J, Kessler JA. Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation. Development. 2004;131:4131\u201342.","journal-title":"Development"},{"key":"8042_CR57","first-page":"632","volume":"21","author":"Y Jia","year":"2018","unstructured":"Jia Y, Hu R, Li P, Zheng Y, Wang Y, Ma X. DEC1 is required for anti-apoptotic activity of gastric cancer cells under hypoxia by promoting Survivin expression. Gastric Cancer J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2018;21:632\u201342.","journal-title":"Gastric Cancer J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc"},{"key":"8042_CR58","doi-asserted-by":"publisher","first-page":"4058","DOI":"10.1073\/pnas.070526297","volume":"97","author":"H Sun","year":"2000","unstructured":"Sun H, Taneja R. Stra13 expression is associated with growth arrest and represses transcription through histone deacetylase (HDAC)-dependent and HDAC-independent mechanisms. Proc Natl Acad Sci USA. 2000;97:4058\u201363.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8042_CR59","doi-asserted-by":"crossref","unstructured":"Doheny D, Manore SG, Wong GL, Lo HW. Hedgehog signaling and truncated GLI1 in cancer. Cells. 2020;9:2114.","DOI":"10.3390\/cells9092114"},{"key":"8042_CR60","doi-asserted-by":"publisher","first-page":"2454","DOI":"10.1101\/gad.1693608","volume":"22","author":"M Varjosalo","year":"2008","unstructured":"Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22:2454\u201372.","journal-title":"Genes Dev"},{"key":"8042_CR61","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.canlet.2021.06.007","volume":"518","author":"V Koh","year":"2021","unstructured":"Koh V, Chakrabarti J, Torvund M, Steele N, Hawkins JA, Ito Y, et al. Hedgehog transcriptional effector GLI mediates mTOR-Induced PD-L1 expression in gastric cancer organoids. Cancer Lett. 2021;518:59\u201371.","journal-title":"Cancer Lett"},{"key":"8042_CR62","doi-asserted-by":"publisher","first-page":"e111338","DOI":"10.1371\/journal.pone.0111338","volume":"9","author":"S Marwaha","year":"2014","unstructured":"Marwaha S, Schumacher MA, Zavros Y, Eghbalnia HR. Crosstalks between cytokines and Sonic Hedgehog in Helicobacter pylori infection: a mathematical model. PloS One. 2014;9:e111338.","journal-title":"PloS One"},{"key":"8042_CR63","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1002\/ijc.22835","volume":"121","author":"A Shiotani","year":"2007","unstructured":"Shiotani A, Uedo N, Iishi H, Tatsuta M, Ishiguro S, Nakae Y, et al. Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia. Int J Cancer. 2007;121:1182\u20139.","journal-title":"Int J Cancer"},{"key":"8042_CR64","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.4161\/cbt.4.10.2184","volume":"4","author":"Y Katoh","year":"2005","unstructured":"Katoh Y, Katoh M. Hedgehog signaling pathway and gastric cancer. Cancer Biol Ther. 2005;4:1050\u20134.","journal-title":"Cancer Biol Ther"},{"key":"8042_CR65","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1111\/febs.15461","volume":"288","author":"H Wang","year":"2021","unstructured":"Wang H, Meng Q, Ding Y, Xiong M, Zhu M, Yang Y, et al. USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines. FEBS J. 2021;288:1325\u201342.","journal-title":"FEBS J"},{"key":"8042_CR66","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.29132","volume":"95","author":"H Zhao","year":"2023","unstructured":"Zhao H, Wei Y, Zhang J, Zhang K, Tian L, Liu Y, et al. HPV16 infection promotes the malignant transformation of the esophagus and progression of esophageal squamous cell carcinoma. J Med Virol. 2023;95:e29132.","journal-title":"J Med Virol"},{"key":"8042_CR67","doi-asserted-by":"publisher","first-page":"3974","DOI":"10.1158\/1078-0432.CCR-14-0011","volume":"20","author":"C Yoon","year":"2014","unstructured":"Yoon C, Park DJ, Schmidt B, Thomas NJ, Lee HJ, Kim TS, et al. CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin Cancer Res J Am Assoc Cancer Res. 2014;20:3974\u201388.","journal-title":"Clin Cancer Res J Am Assoc Cancer Res"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08042-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08042-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08042-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T21:09:05Z","timestamp":1759871345000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08042-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8042"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-08042-9","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]},"assertion":[{"value":"22 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 August 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal experiments were approved by the Committee for Animal Research of Jinan Central Hospital. The approval ID for the use of animals was W202303090259. The gastric cancer tissue samples used in the study were derived from patients who gave written informed consent for the use of the specimen. The studies were approved by the Medical Ethics Committee of Jinan Central Hospital.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"713"}}