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Background  Histone H2AX phosphorylation at the site of Tyr-142 can participates in multiple biological progressions, which is including DNA repair. Ras pathway is closely involved in human cancers. Our study investigated the effects of Ras pathway via regulating H2AX. Y142ph .    Methods  Gastric cancer cell line SNU-16 and MKN1 cells were transfected with Ras for G12D and T35S site mutation. The phosphorylation of H2A.X Y142  and ERK1/2, WSTF and MDM2 was detected by western blot. Cell viability, cell colonies and migration was analyzed by MTT assay, soft-agar colony formation assay, and Transwell assay, respectively. The expression of Ras pathway related downstream factors, EYA3 and WSTF was detected by qRT-PCR. The relationship between Ras and downstream factors were detected by ChIP. The cell cycle progression was measured by flow cytometry.    Results  Ras G12D/T35V  transection decreased the phosphorylation of H2A.X Y142  and activated phosphorylation of ERK-1/2. H2A.X Y142  inhibited cell viability, colonies and migration. H2A.X Y142ph  altered the expression of Ras downstream factors. CHIP assay revealed that Ras G12D/T35V  could bind to the promoters of these Ras pathway downstream factors. Silence of EYA3 increased H2A.X Y142ph  and inhibited cell viability, migration and percent cells in S stage. Furthermore, silence of EYA3 also changed the downstream factors expression. WSTF and H2A.X Y142ph  revealed the similar trend and MDM2 on the opposite.    Conclusion  Ras/ERK signal pathway decreased H2A.X Y142ph  and promoted cell growth and metastasis. This Ras regulation process was down-regulated by the cascade of MDM2-WSTF-EYA3 to decrease H2A.X Y142ph  in SNU-16 cells.

RETRACTED ARTICLE: K-ras-ERK1/2 down-regulates H2A.XY142ph through WSTF to promote the progress of gastric cancer