Potential conflict of interest: Nothing to report.
Epigenetic silencing of DACH1 induces loss of transforming growth factor-β1 antiproliferative response in human hepatocellular carcinoma
Article first published online: 21 OCT 2013
Copyright © 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 6, pages 2012–2022, December 2013
How to Cite
Zhu, H., Wu, K., Yan, W., Hu, L., Yuan, J., Dong, Y., Li, Y., Jing, K., Yang, Y. and Guo, M. (2013), Epigenetic silencing of DACH1 induces loss of transforming growth factor-β1 antiproliferative response in human hepatocellular carcinoma. Hepatology, 58: 2012–2022. doi: 10.1002/hep.26587
Supported by grants from the National Basic Research Program of China (973 Program Nos. 2012CB934002, 2010CB912802); National High-tech R&D Program of China (863 Program Nos. SS2012AA020314, SS2012AA020821, SS2012AA020303); National Key Scientific Instrument Special Programme of China (Grant No. 2011YQ03013405); National Science Foundation of China (Grant Nos. 81121004, 81071953, 81161120432, 81072169, 81172422, 81261120395).
- Issue published online: 26 NOV 2013
- Article first published online: 21 OCT 2013
- Accepted manuscript online: 20 JUN 2013 08:23AM EST
- Manuscript Accepted: 9 JUN 2013
- Manuscript Received: 20 JAN 2013
Human dachshund homolog 1 (DACH1) is a major component of the Retinal Determination Gene Network (RDGN) and functions as a tumor suppressor. However, the regulation of DACH1 expression and its function in hepatocellular carcinoma (HCC) remain unclear. In this study, epigenetic changes of DACH1 were analyzed in HCC cell lines and primary cancers. We found that promoter region hypermethylation was correlated with loss or reduction of DACH1 expression, and restoration of DACH1 expression was induced by 5-aza-2′-deoxycytidine (5-AZA) in HCC cell lines. Promoter region methylation was found in 42% of primary HCC. Reduced expression of DACH1 was associated with poor differentiation of HCC nodules and higher serum aspartate aminotransferase/alanine aminotransferase ratio. DACH1 suppressed cellular growth by reactivating transforming growth factor beta (TGF-β) signaling. Ectopic expression of DACH1 enhanced chemosensitivity to 5-fluorouracil (5-FU) by inducing p21 expression in HCC cells. Conclusion: DACH1 is frequently methylated in HCC and DACH1 expression is regulated by promoter hypermethylation. Down-regulation of DACH1 is a novel mechanism for gaining resistance to the antiproliferative signaling of TGF-β1 and 5-FU resistance. (Hepatology 2013; 58:2012–2022)