title: ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells.
abstract: Liver cancer stem cells (CSCs) have been identified and shown to have self-renewal and differentiation properties; however, the biology of these hepatic CSCs remains largely unknown. Here, we analyzed transcriptome gene expression profiles of liver CSCs and non-CSCs from hepatocellular carcinoma (HCC) cells lines and found that the transcription factor (TF) ZIC2 is highly expressed in liver CSCs. ZIC2 was required for the self-renewal maintenance of liver CSCs, as ZIC2 depletion reduced sphere formation and xenograft tumor growth in mice. We determined that ZIC2 acts upstream of the TF OCT4 and that ZIC2 recruits the nuclear remodeling factor (NURF) complex to the OCT4 promoter, thereby initiating OCT4 activation. In HCC patients, expression levels of the NURF complex were consistent with clinical severity and prognosis. Moreover, ZIC2 and OCT4 levels positively correlated to the clinicopathological stages of HCC patients. Altogether, our results indicate that levels of ZIC2, OCT4, and the NURF complex can be detected and used for diagnosis and prognosis prediction of HCC patients. Moreover, these factors may be potential therapeutic targets for eradicating liver CSCs.
authors.forename: Pingping
authors.initials: P
authors.lastname: Zhu
authors.forename: Yanying
authors.initials: Y
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: He
authors.forename: Guanling
authors.initials: G
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Du
authors.forename: Geng
authors.initials: G
authors.lastname: Zhang
authors.forename: Xinlong
authors.initials: X
authors.lastname: Yan
authors.forename: Pengyan
authors.initials: P
authors.lastname: Xia
authors.forename: Buqing
authors.initials: B
authors.lastname: Ye
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Hao
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wu
authors.forename: Zusen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D064113:CRISPR-Cas Systems; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000502:physiology*; D042002:Chromatin Assembly and Disassembly; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000502:physiology*; D050814:Octamer Transcription Factor-3 / Q000502:physiology*; D025941:Protein Interaction Mapping; D056505:Retinoblastoma-Binding Protein 4 / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D000092468:Bromodomain Containing Proteins
chemical_list: D034961:Antigens, Nuclear; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; D056505:Retinoblastoma-Binding Protein 4; D014157:Transcription Factors; C494173:POU5F1 protein, human; C082637:RBBP4 protein, human; C491812:ZIC2 protein, human; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins