title: Epigenetic regulation of pluripotent genes mediates stem cell features in human hepatocellular carcinoma and cancer cell lines.
abstract: Activation of the stem cell transcriptional circuitry is an important event in cancer development. Although cancer cells demonstrate a stem cell-like gene expression signature, the epigenetic regulation of pluripotency-associated genes in cancers remains poorly understood. In this study, we characterized the epigenetic regulation of the pluripotency-associated genes NANOG, OCT4, c-MYC, KLF4, and SOX2 in a variety of cancer cell lines and in primary tumor samples, and investigated the re-activation of pluripotency regulatory circuits in cancer progression. Differential patterns of DNA methylation, histone modifications, and gene expression of pluripotent genes were demonstrated in different types of cancers, which may reflect their tissue origins. NANOG promoter hypomethylation and gene upregulation were found in metastatic human liver cancer cells and human hepatocellular carcinoma (HCC) primary tumor tissues. The upregulation of NANOG, together with p53 depletion, was significantly associated with clinical late stage of HCC. A pro-metastatic role of NANOG in colon cancer cells was also demonstrated, using a NANOG-overexpressing orthotopic tumor implantation mouse model. Demethylation of NANOG promoter was observed in CD133+(high) cancer cells. In accordance, overexpression of NANOG resulted in an increase in the population of CD133+(high) cells. In addition, we demonstrated a cross-regulation between OCT4 and NANOG in cancer cells via reprogramming of promoter methylation. Taken together, epigenetic reprogramming of NANOG can lead to the acquisition of stem cell-like properties. These results underscore the restoration of pluripotency circuits in cancer cells as a potential mechanism for cancer progression.
authors.affiliation: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China ; State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Xiao Qi
authors.initials: XQ
authors.lastname: Wang
authors.forename: Ray Kit
authors.initials: RK
authors.lastname: Ng
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ming
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Andrew C Y
authors.initials: AC
authors.lastname: Chu
authors.forename: Roberta
authors.initials: R
authors.lastname: Pang
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Xuqing
authors.initials: X
authors.lastname: Liu
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology*; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005434:Flow Cytometry; D045325:HCT116 Cells; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008113:Liver Neoplasms / Q000453:epidemiology*; D051379:Mice; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D016159:Tumor Suppressor Protein p53
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