Zhang Xiaomei, Yang Yunsheng, Liu Xuefeng, Herman James G, Brock Malcolm V, Licchesi Julien D F, Yue Wen, Pei Xuetao, Guo Mingzhou
Department of Gastroenterology & Hepatology; Chinese PLA General Hospital; Beijing, P.R. China.
The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Johns Hopkins University; Baltimore, MD USA.
Epigenetics. 2013 Apr;8(4):373-82. doi: 10.4161/epi.24113. Epub 2013 Feb 28.
DACT2 (Dapper, Dishevelled-associated antagonist of β-catenin homolog 2) is a member of the DACT family involved in the regulation of embryonic development. Human DACT2 is localized on 6q27, a region of frequent loss of heterozygosity in human cancers. However, the regulation of DACT2 expression and function in hepatocellular carcinoma (HCC) remains unclear. In this study, genetic and epigenetic changes of DACT2 were analyzed in HCC cell lines and primary cancer. We found no single-nucleotide polymorphism (SNP) associated with HCC. Promoter region methylation was correlated with loss or reduction of DACT2 expression, and restoration of DACT2 expression was induced by 5-aza-2'-deoxycytidine (5-AZA) in HCC cell lines. Promoter region methylation was found in 54.84% of primary HCC. Reduction of DACT2 expression was associated with promoter hypermethylation, and expression of DACT2 was inversely related to β-catenin expression in primary HCC. DACT2 suppressed cell proliferation, induced G 2-M arrest in cell lines and inhibited tumor growth in xenograft nude mice. The transcriptional activity of TCF-4 and the expression of Wnt signaling downstream genes were suppressed by DACT2 re-expression and reactivated by depletion of DACT2. In conclusion, DACT2 is frequently methylated in HCC and its expression is regulated by promoter hypermethylation. DACT2 suppresses HCC by inhibiting Wnt signaling in human HCC.
DACT2（β-连环蛋白同源物2的Dapper、紊乱相关拮抗剂）是参与胚胎发育调控的DACT家族成员。人类DACT2定位于6q27，该区域在人类癌症中经常出现杂合性缺失。然而，DACT2在肝细胞癌（HCC）中的表达和功能调控仍不清楚。在本研究中，分析了HCC细胞系和原发性癌中DACT2的遗传和表观遗传变化。我们未发现与HCC相关的单核苷酸多态性（SNP）。启动子区域甲基化与DACT2表达的缺失或降低相关，并且在HCC细胞系中，5-氮杂-2'-脱氧胞苷（5-AZA）可诱导DACT2表达的恢复。在54.84%的原发性HCC中发现了启动子区域甲基化。DACT2表达的降低与启动子高甲基化相关，并且在原发性HCC中，DACT2的表达与β-连环蛋白的表达呈负相关。DACT2抑制细胞增殖，在细胞系中诱导G2-M期阻滞，并抑制异种移植裸鼠中的肿瘤生长。DACT2的重新表达可抑制TCF-4的转录活性以及Wnt信号下游基因的表达，而DACT2的缺失则可使其重新激活。总之，DACT2在HCC中经常发生甲基化，其表达受启动子高甲基化调控。DACT2通过抑制人类HCC中的Wnt信号来抑制HCC。
