title: Epigenetic silencing of DACH1 induces the invasion and metastasis of gastric cancer by activating TGF-β signalling.
abstract: Gastric cancer (GC) is the fourth most common malignancy in males and the fifth most common malignancy in females worldwide. DACH1 is frequently methylated in hepatic and colorectal cancer. To further understand the regulation and mechanism of DACH1 in GC, eight GC cell lines, eight cases of normal gastric mucosa, 98 cases of primary GC and 50 cases of adjacent non-tumour tissues were examined. Methylation-specific PCR, western blot, transwell assay and xenograft mice were used in this study. Loss of DACH1 expression correlated with promoter region methylation in GC cells, and re-expression was induced by 5-Aza-2'-deoxyazacytidine. DACH1 is methylated in 63.3% (62/98) of primary GC and 38% (19/50) of adjacent non-tumour tissues, while no methylation was found in normal gastric mucosa. Methylation of DACH1 correlated with reduced expression of DACH1 (P < 0.01), late tumour stage (stage III/IV) (P < 0.01) and lymph node metastasis (P < 0.05). DACH1 expression inhibited epithelial-mesenchymal transition and metastasis by inhibiting transforming growth factor (TGF)-β signalling and suppressed GC cell proliferation through inducing G2/M phase arrest. The tumour size is smaller in DACH1-expressed BGC823 cell xenograft mice than in unexpressed group (P < 0.01). Restoration of DACH1 expression also sensitized GC cells to docetaxel. These studies suggest that DACH1 is frequently methylated in human GC and expression of DACH1 was controlled by promoter region methylation. DACH1 suppresses GC proliferation, invasion and metastasis by inhibiting TGF-β signalling pathways both in vitro and in vivo. Epigenetic silencing DACH1 may induce GC cells' resistance to docetaxel.
authors.affiliation: Institute of Digestive Diseases, Chinese PLA General Hospital, Beijing, China.
authors.forename: Wenji
authors.initials: W
authors.lastname: Yan
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.forename: Yusen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Youyong
authors.initials: Y
authors.lastname: Lu
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Yang
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Guo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C486747:DACH1 protein, human; D005136:Eye Proteins; D043823:Taxoids; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000077143:Docetaxel
keywords: DACH1; DNA methylation; chemosensitive marker; docetaxel; gastric cancer; invasion; metastasis