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

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. What's new? DNA hypomethylation can promote cancer development through activation of genes with oncogenic potential. Here, the authors found that CpGs in the promoter‐proximal DNA of ONECUT2 were hypomethylated in intestinal metaplasia and gastric cancers, and that hypomethylation was associated with ONECUT2 upregulation. Functional analysis demonstrated that ONECUT2 has oncogenic potential and could activate ACSL5, which is also expressed in intestinal metaplasia, suggesting that ONECUT2 and ACSL5 may cooperate to promote intestinal differentiation or development of gastric cancer. Taken together, the findings suggest that ONECUT2 and its downstream target ACSL5 could be used to develop early detection biomarkers and prevent gastric carcinogenesis.