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Many studies have focused on global hypomethylation or hypermethylation of tumor suppressor genes, but less is known about the impact of promoter hypomethylation of oncogenes. We previously showed that promoter methylation may gradually increase or decrease during the transition from gastric mucosa (GM) to intestinal metaplasia (IM) to gastric cancer (GC). In our study, we focused on regional CpG hypomethylation of the promoter‐proximal DNA of the transcription factor  ONECUT2  ( OC2 ) in IM and GC cells. We validated the hypomethylation of promoter‐proximal DNA of  OC2  in 160 primary GCs, in which methylation level correlated negatively with  OC2  mRNA level. IM and GC cells stained positively for OC2, whereas GM cells did not. Stable transfection of  OC2  in GC cells promoted colony formation, cell migration, invasion and proliferation. Moreover,  OC2  knockdown with a short hairpin RNA suppressed tumorigenesis in nude mice. In addition, chromatin immunoprecipitation coupled with DNA sequencing and RNA‐seq analyses revealed that  OC2  triggered  ACSL5 , which is strongly expressed in IM of the stomach but not in GM, indicating that  OC2  and  ACSL5  are early‐stage biomarkers for GC. We also observed a high correlation between the levels of  OC2  and  ACSL5  mRNAs in the GENT database These results suggest that epigenetic alteration of  OC2  upregulates its expression, which then activates  ACSL5 ; thus,  OC2  is induced in IM by epigenetic alteration and triggers  ACSL5  expression, and thus  OC2  and  ACSL5  may cooperatively promote intestinal differentiation and GC progression.

ONECUT2 upregulation is associated with CpG hypomethylation at promoter‐proximal DNA in gastric cancer and triggers ACSL5