title: Epigenetic silencing of DACH1 induces loss of transforming growth factor-β1 antiproliferative response in human hepatocellular carcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, P.R. China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Zhu
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.forename: Wenji
authors.initials: W
authors.lastname: Yan
authors.forename: Ling
authors.initials: L
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Li
authors.forename: Kunyu
authors.initials: K
authors.lastname: Jing
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Yang
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Guo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000503:physiopathology*; D019175:DNA Methylation; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C486747:DACH1 protein, human; D005136:Eye Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D001374:Azacitidine; D005472:Fluorouracil