Abstract
Helicobacter pylori (H. pylori) 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 H. pylori-infected gastric tissues and associated with prognosis of gastric cancer (GC). H. pylori 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 H. pylori-mediated tumorigenic activities in vitro cellular and in vivo tumor-bearing mouse models. Moreover, H. pylori 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 H. pylori 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 H. pylori-mediated gastric tumorigenesis through dysregulation of DEC1/SHH/GLI1 axis, which provides potential therapeutic targets in GC.