title: ZIC1 is downregulated through promoter hypermethylation, and functions as a tumor suppressor gene in colorectal cancer.
abstract: The transcription factor, Zinc finger of the cerebellum (ZIC1), plays a crucial role in vertebrate development. Recently, ZIC1 has also been found to participate in the progression of human cancers, including medulloblastomas, endometrial cancers, and mesenchymal neoplasms. However, the function of ZIC1 in colon cancer progression has not been defined. In this study, we demonstrate ZIC1 to be silenced or significantly downregulated in colon cancer cell lines. These effects were reversed by demethylation treatment with 5-aza-2'-deoxycytidine (Aza). ZIC1 expression is also significantly downregulated in primary colorectal cancer tissues relative to adjacent non-tumor tissues (p = 0.0001). Furthermore, methylation of ZIC1 gene promoter is frequently detected in primary tumor tissues (85%, 34/40), but not in adjacent non-tumor tissues. Ectopic expression of ZIC1 suppresses cell proliferation and induces apoptosis, which is associated with MAPK and PI(3)K/Akt pathways, as well as the Bcl-xl/Bad/Caspase3 cascade. To identify target candidates of ZIC1, we employed cDNA microarray and found that 337 genes are downregulated and 95 genes upregulated by ectopic expression of ZIC1, which were verified by 10 selected gene expressions by qRT-PCR. Taken together, our results suggest that ZIC1 may potentially function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in colorectal cancers.
authors.affiliation: Department of Gastroenterology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Gan
authors.forename: Shujie
authors.initials: S
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Zhong
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Emily K Y
authors.initials: EK
authors.lastname: Lam
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Jianbin
authors.initials: J
authors.lastname: Zhang
authors.forename: Tianhua
authors.initials: T
authors.lastname: Zhou
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Jianmin
authors.initials: J
authors.lastname: Si
authors.forename: Liangjing
authors.initials: L
authors.lastname: Wang
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Jin
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
chemical_list: D014157:Transcription Factors; C492123:ZIC1 protein, human