Epigenetic silencing of DACH1 induces the invasion and metastasis of gastric cancer by activating TGF-β signalling
Article first published online: 9 JUN 2014
© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Journal of Cellular and Molecular Medicine
Volume 18, Issue 12, pages 2499–2511, December 2014
How to Cite
Yan, W., Wu, K., Herman, J. G., Brock, M. V., Zhou, Y., Lu, Y., Zhang, Z., Yang, Y. and Guo, M. (2014), Epigenetic silencing of DACH1 induces the invasion and metastasis of gastric cancer by activating TGF-β signalling. Journal of Cellular and Molecular Medicine, 18: 2499–2511. doi: 10.1111/jcmm.12325
- Issue published online: 21 NOV 2014
- Article first published online: 9 JUN 2014
- Manuscript Accepted: 23 APR 2014
- Manuscript Received: 31 DEC 2013
- National Basic Research Program of China. Grant Numbers: 2012CB934002, 2010CB912802
- National High-tech R&D Program of China. Grant Numbers: SS2012AA020314, SS2012AA020821, SS2012AA020303
- National Key Scientific Instrument Special Programme of China. Grant Number: 2011YQ03013405
- National Science Foundation of China. Grant Numbers: 81121004, 81071953, 81161120432, 81072169, 81172422, 81261120395
- DNA methylation;
- gastric cancer;
- chemosensitive marker;
Gastric cancer (GC) is the fourth most common malignancy in males and the fifth most common malignancy in females worldwide. DACH1 is frequently methylated in hepatic and colorectal cancer. To further understand the regulation and mechanism of DACH1 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 DACH1 expression correlated with promoter region methylation in GC cells, and re-expression was induced by 5-Aza-2′-deoxyazacytidine. DACH1 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 DACH1 correlated with reduced expression of DACH1 (P < 0.01), late tumour stage (stage III/IV) (P < 0.01) and lymph node metastasis (P < 0.05). DACH1 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 BGC823 cell xenograft mice than in unexpressed group (P < 0.01). Restoration of DACH1 expression also sensitized GC cells to docetaxel. These studies suggest that DACH1 is frequently methylated in human GC and expression of DACH1 was controlled by promoter region methylation. DACH1 suppresses GC proliferation, invasion and metastasis by inhibiting TGF-β signalling pathways both in vitro and in vivo. Epigenetic silencing DACH1 may induce GC cells' resistance to docetaxel.