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ONECUT2 is a putative oncogene associated with CpG hypomethylation at promoter-proximal DNA in gastric cancer and triggers ACSL5, a member of the ACS family

ABSTRACT: To access methylation change during gastric carcinogenesis in this study, we performed RRBS analysis with LCM-derived normal gastric mucosa and gastric tumor tissue [GSE55159]. Among a set of genes hypomethylated and upregulated in GC, ONECUT2 was identified as a hypomethylated target in GC. Upregulated ONECUT2 expression significantly increased the proliferation, colony formation, migration and invasion in GC cells. To identify target genes regulated by ONECUT2, we performed ChIP-seq and RNA-seq.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113045 | GEO | 2020/02/16

REPOSITORIES: GEO

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Project description:Background: Helicobacter pylori (HP) infection may initiate and promote progression of gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Methods: Public data, single-cell RNA sequencing, spatial transcriptome analysis, RNA sequencing, GC tissue specimens, and clinical survival data were analyzed. Human GC organoids, HP infection, 3D sphere-forming, and extreme-dilution nude mouse models were constructed. Western blotting, qPCR, immunohistochemical staining, dual-luciferase reporter assays, phosphokinase microarray, and immunofluorescence were used. Results: Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increases stemness in GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/β-catenin phosphorylation. AKT/β-catenin phosphorylation facilitates β-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cell. HP infection could upregulate the phosphorylation of AKT and β-catenin triggered by ONECUT2 downregulation via induction of ONECUT2. Clinical survival analysis indicated that high ONECUT2 expression might be an indicator of poor prognosis in GC. Conclusion: This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/β-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential therapeutic targets for GC treatment. Keywords: Helicobacter pylori; gastric cancer; prognosis; tumor stemness; ONECUT2

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ONECUT2 is a putative oncogene associated with CpG hypomethylation at promoter-proximal DNA in gastric cancer and triggers ACSL5, a member of the ACS family

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