942 Epigenetic Silencing of DACH1 Induces the Invasion and Migration of Gastric Cancer by Activating TGF-β Signaling

Abstract

Gastric cancer (GC) is the fourth most common malignancy in males and the fifth most common malignancy in females worldwide and a leading cause of cancer death. Loss of DACH1 expression was found in breast, prostate, endometrial cancer, hepatocellular carcinoma and colorectal cancer. To analyze the regulation and the function of DACH1 in GC, 8 gastric cancer cell lines, 8 cases of normal mucosa and 98 cases of primary GC were employed in this study. Loss of DACH1 expression is correlated with promoter region hypermethylation and re-expression of DACH1 was induced by 5-Aza-2'-deoxyazacytidine treatment in GC cell lines. DACH1 is frequently methylated in primary GC and methylation of DACH1 is associated with reduction of DACH1 expression (p<0.01). These results suggest that DACH1 expression was regulated by promoter region hypermethylation in GC. DACH1 methylation was associated with late tumor stage (p<0.01) and lymph node metastasis (p<0.05). Re-expression of DACH1 suppressed SBE4 luciferase reporter activity and inhibited TGF-β signaling by reducing the level of phosphorylated Smad2. DACH1 inhibited epithelialmesenchymal transition (EMT) and metastasis of GC by inhibition of TGF-β signaling. The tumor size is smaller in DACH1 re-expressed BGC823 cell xenograft than in control group (p<0.01). Restoration of DACH1 expression induced G2/M phase arrest and sensitized GC cells to docetaxel. In conclusion, DACH1 is frequently methylated in human GC and methylation of DACH1 may serve as detective and prognostic markers in GC. DACH1 serve as a tumor suppresser both in vitro and in vivo, suppressed GC metastasis by inhibiting TGFβ signaling. Silencing of DACH1 expression may cause resistance of GC cells to docetaxel.