Abstract
Gastrokine 1 (GKN1) is a gastric mucosal protein highly expressed and secreted in normal individuals but during Helicobacter pylori infection or in gastric carcinogenesis it is strongly down-regulated or totally absent. In gastric cancer, the GKN1 gene is silenced through an epigenetic mechanism most likely mediated by a transcription factor that promotes on GKN1 promoter the activity of the enzymes SUV39H1 and HDACs. Because RUNX3 is a potential candidate in the regulation of molecular carcinogenesis process of stomach cancers, we tried to assess if RUNX3 could be involved in GKN1 down-regulation in GC. 17 paired of non-tumoral and tumoral surgical specimens from patients with gastric cancer were analyzed for GKN1 and RUNX3 by Western blotting and chromatin immunoprecipitation (Chip) assays. The overall results indicated that RUNX3 expression was not associated with the down-regulation of GKN1. The expression levels of RUNX3 in non-tumoral and tumoral samples suggest that RUNX3 does not act as a tumor suppressor but that it might play a complex oncogenic role in gastric cancer cells.
Highlights
Because RUNX3 is a potential candidate in the regulation of molecular carcinogenesis process of stomach cancers, we tried to assess if RUNX3 could be involved in Gastrokine 1 (GKN1) down-regulation in GC. 17 paired of non-tumoral and tumoral surgical specimens from patients with gastric cancer were analyzed for GKN1 and RUNX3 by Western blotting and chromatin immunoprecipitation (Chip) assays
We showed that epigenetic mechanisms leading to the inactivation of GKN1 gene play a key role in the multi-step process of gastric carcinogenesis
We propose a model in which a transcription factor might functions as a negative regulator by recruiting on the GKN1 promoter Histone-lysine N-methyltransferase (SUV39H1) and histone deacetylase (HDAC) to induce histone methylation and deacetylation, respectively resulting in GKN1 inactivation (Figure 1)
Summary
Chromatin immunoprecipitation assays for the trimethylation of histone 3 at lysine 9 (H3K9triMe) and its specific histone-lysine N-methyltransferase (SUV39H1), performed on human specimens of normal and cancerous gastric tissues, showed that GKN1 down-regulation in GC tissues was associated with high levels of H3K9triMe and with the recruitment of SUV39H1 to the GKN1 promoter. These findings suggested that an epigenetic transcriptional complex could negatively regulate GKN1 expression in gastric tumors [7]. These data denoted that RUNX3 might be in GC an oncogene [9] [10] [11] [12] rather than a tumor suppressor [10]
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