title: ZIC1 is downregulated through promoter hypermethylation in gastric cancer.
abstract: As one of major epigenetic changes responsible for tumor suppressor gene inactivation in the development of cancer, promoter hypermethylation was proposed as a marker to define novel tumor suppressor genes. In the current study we identified ZIC1 (Zic family member 1, odd-paired Drosophila homolog) as a novel tumor suppressor gene silenced through promoter hypermethylation in gastric cancer, the second leading cause of cancer death worldwide. In all of gastric cancer cells lines examined, ZIC1 expression was downregulated and such downregulation was accompanied with the hypermethylation of ZIC1 promoter. Demethylation treatment with 5-aza-2'-deoxycytidine (Aza) reversed ZIC1 downregulation, highlighting the importance of promoter methylation to ZIC1 downregulation in gastric cancer cells. Notably, ZIC1 expression was significantly downregulated in primary gastric carcinoma tissues in comparison with non-tumor adjacent gastric tissues (p<0.01). Accordingly, promoter methylation of ZIC1 was frequently detected in primary gastric carcinoma tissues (94.6%, 35/37) but not normal gastric tissues, indicating that promoter hypermethylation mediated ZIC1 downregulation may play an important role in gastric carcinogenesis. Indeed, ectopic expression of ZIC1 led to the growth inhibition of gastric cancer cells through the induction of S-phase cell cycle arrest (p<0.01). Our results revealed ZIC1 as a novel candidate tumor suppressor gene downregulated through promoter hypermethylation in gastric cancer.
authors.affiliation: Department of Gastroenterology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Liang Jing
authors.initials: LJ
authors.lastname: Wang
authors.forename: Hong Chuan
authors.initials: HC
authors.lastname: Jin
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Emily K Y
authors.initials: EK
authors.lastname: Lam
authors.forename: Jian Bin
authors.initials: JB
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Francis K L
authors.initials: FK
authors.lastname: Chan
authors.forename: Jian Min
authors.initials: JM
authors.lastname: Si
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C492123:ZIC1 protein, human