ZIC1 is downregulated through promoter hypermethylation, and functions as a tumor suppressor gene in colorectal cancer

• Published in: PloS one 2011-02, Vol.6 (2), p.e16916-e16916
• Main Authors: Gan, Lihong, Chen, Shujie, Zhong, Jing, Wang, Xian, Lam, Emily K Y, Liu, Xin, Zhang, Jianbin, Zhou, Tianhua, Yu, Jun, Si, Jianmin, Wang, Liangjing, Jin, Hongchuan
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Angiogenesis; Apoptosis; Apoptosis - genetics; Bcl-x protein; Biology; Biomedical research; Breast cancer; Cancer; Cancer genetics; Cell Line, Tumor; Cell Proliferation; Cerebellum; Colon; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Demethylation; Deoxyribonucleic acid; Development and progression; DNA; DNA binding proteins; DNA methylation; DNA Methylation - genetics; DNA microarrays; Down-Regulation - genetics; Ectopic expression; Endometrial cancer; Endometrium; Epigenetics; Female; Gastric cancer; Gastroenterology; Gene expression; Gene Silencing; Genes; Genes, Tumor Suppressor; Genetic aspects; Humans; Laboratories; Male; MAP kinase; Medicine; Melanoma; Mesenchyme; Metastasis; Methylation; Middle Aged; Neoplasia; Neoplasms; Promoter Regions, Genetic - genetics; Proteins; Skin cancer; Stomach cancer; Target recognition; Tissues; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptome - genetics; Trends; Tumor cell lines; Tumor suppressor genes; Tumors; Zinc; Zinc finger proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0016916

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.