Abstract
Abstract Gastrokine 1 (GKN1) functions to protect the gastric antral mucosa and promotes healing by facilitating restitution and proliferation after injury. GKN1 is down-regulated in Helicobacter pylori-infected gastric epithelial cells and that loss of GKN1 expression is tightly associated with gastric carcinogenesis, but underlying mechanisms as tumor suppressor are largely unknown. In the present study, we demonstrated that restoration of GKN1 protein suppressed gastric cancer cell growth by inducing endogenous miR-185 that directly targets epigenetic effectors, DNMT1 and EZH2 in gastric cancer cells. Notably, GKN1 expression was inversely correlated with DNMT1 and EZH2 expression in a subset of gastric cancer tissues and various gastric cancer cell lines. In addition, ectopic expression of GKN1 suppressed histone deacetylase 1 and thereby induced cell cycle arrest via regulating cell cycle proteins in gastric cancer cells. Interestingly, it was found that regulatory domains of the GKN1, pGKN1D13N, pGKN1▵68-199 and pGKN1▵1-67, 165-199 recapitulated GKN1 functions, and GKN1 exerted synergistic anti-cancer effect with 5-FU on tumor cell growth implying that the amino-terminal regulatory motif and brichos domain of GKN1 are sufficient for its tumor suppressor activities and thereby suggesting therapeutic intervention of gastric cancer. Collectively, our results demonstrated that loss of GKN1 functions occur and that cause aberrant expression of DMNT1 and EZH2 by suppression of endogenous miR-185 contributing malignant gastric epithelial cell proliferation and transformation in gastric carcinogenesis. Citation Format: Jung Hwan Yoon, Won Suk Choi, Won Sang Park, Olga Kim. GKN1-miR-185-DNMT1 axis suppresses gastric carcinogenesis through regulation of epigenetic alteration and cell cycle. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1995. doi:10.1158/1538-7445.AM2013-1995
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