Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, P.R. China.
Hepatology. 2013 Dec;58(6):2012-22. doi: 10.1002/hep.26587. Epub 2013 Oct 21.
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.
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.
人类达克斯猎犬同源物 1（DACH1）是视网膜决定基因网络（RDGN）的主要组成部分，具有肿瘤抑制因子的作用。然而，DACH1 表达的调控及其在肝细胞癌（HCC）中的功能尚不清楚。在本研究中，分析了 HCC 细胞系和原发性癌症中 DACH1 的表观遗传变化。我们发现启动子区域超甲基化与 DACH1 表达的缺失或减少相关，并且在 HCC 细胞系中，5-氮杂-2'-脱氧胞苷（5-AZA）可诱导 DACH1 表达的恢复。在 42%的原发性 HCC 中发现启动子区域甲基化。DACH1 的表达降低与 HCC 结节的低分化和血清天冬氨酸氨基转移酶/丙氨酸氨基转移酶比值较高有关。DACH1 通过重新激活转化生长因子β（TGF-β）信号来抑制细胞生长。在 HCC 细胞中，DACH1 的异位表达通过诱导 p21 表达增强了对 5-氟尿嘧啶（5-FU）的化疗敏感性。
DACH1 在 HCC 中经常发生甲基化，DACH1 的表达受启动子甲基化调控。DACH1 的下调是获得 TGF-β1 和 5-FU 耐药性抗增殖信号的新机制。
