title: Epigenetic regulation of the Wnt signaling inhibitor DACT2 in human hepatocellular carcinoma.
abstract: 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.
authors: Department of Gastroenterology & Hepatology; Chinese PLA General Hospital; Beijing, P.R. China.
authors: Xiaomei
authors: X
authors: Zhang
authors: Department of Gastroenterology & Hepatology; Chinese PLA General Hospital; Beijing, P.R. China.
authors: Yunsheng
authors: Y
authors: Yang
authors: Department of Gastroenterology & Hepatology; Chinese PLA General Hospital; Beijing, P.R. China.
authors: Xuefeng
authors: X
authors: Liu
authors: The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Johns Hopkins University; Baltimore, MD USA.
authors: James G
authors: JG
authors: Herman
authors: The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Johns Hopkins University; Baltimore, MD USA.
authors: Malcolm V
authors: MV
authors: Brock
authors: The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Johns Hopkins University; Baltimore, MD USA.
authors: Julien D F
authors: JD
authors: Licchesi
authors: Stem Cells and Regenerative Medicine Lab; Beijing Institute of Transfusion Medicine; Beijing, P.R. China.
authors: Wen
authors: W
authors: Yue
authors: Stem Cells and Regenerative Medicine Lab; Beijing Institute of Transfusion Medicine; Beijing, P.R. China.
authors: Xuetao
authors: X
authors: Pei
authors: Department of Gastroenterology & Hepatology; Chinese PLA General Hospital; Beijing, P.R. China.
authors: Mingzhou
authors: M
authors: Guo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008745:Methylation; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C478653:DACT2 protein, human; D009363:Neoplasm Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D000077209:Decitabine; D001374:Azacitidine
keywords: DACT2; DNA methylation; Wnt signaling; epigenetics; hepatocellular carcinoma