Open AccessEpigenetic silencing of DACH 1 induces the invasion and metastasis of gastric cancer by activating TGF ‐β signalling
Author(s) -
Yan Wenji,
Wu Kongming,
Herman James G.,
Brock Malcolm V.,
Zhou Yusen,
Lu Youyong,
Zhang Zhiqian,
Yang Yunsheng,
Guo Mingzhou
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12325
Subject(s) - methylation , gene silencing , metastasis , cancer research , microbiology and biotechnology , chemistry , apoptosis , transforming growth factor , cell growth , biology , cancer , medicine , endocrinology , gene , biochemistry
Gastric cancer ( GC ) is the fourth most common malignancy in males and the fifth most common malignancy in females worldwide. DACH 1 is frequently methylated in hepatic and colorectal cancer. To further understand the regulation and mechanism of DACH 1 in GC , eight GC cell lines, eight cases of normal gastric mucosa, 98 cases of primary GC and 50 cases of adjacent non‐tumour tissues were examined. Methylation‐specific PCR, western blot, transwell assay and xenograft mice were used in this study. Loss of DACH 1 expression correlated with promoter region methylation in GC cells, and re‐expression was induced by 5‐Aza‐2′‐deoxyazacytidine. DACH 1 is methylated in 63.3% (62/98) of primary GC and 38% (19/50) of adjacent non‐tumour tissues, while no methylation was found in normal gastric mucosa. Methylation of DACH 1 correlated with reduced expression of DACH 1 ( P < 0.01), late tumour stage (stage III/IV) ( P < 0.01) and lymph node metastasis ( P < 0.05). DACH 1 expression inhibited epithelial–mesenchymal transition and metastasis by inhibiting transforming growth factor ( TGF )‐β signalling and suppressed GC cell proliferation through inducing G2/M phase arrest. The tumour size is smaller in DACH1‐expressed BGC 823 cell xenograft mice than in unexpressed group ( P < 0.01). Restoration of DACH 1 expression also sensitized GC cells to docetaxel. These studies suggest that DACH 1 is frequently methylated in human GC and expression of DACH 1 was controlled by promoter region methylation. DACH 1 suppresses GC proliferation, invasion and metastasis by inhibiting TGF ‐β signalling pathways both in vitro and in vivo . Epigenetic silencing DACH 1 may induce GC cells' resistance to docetaxel.