ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells

J Clin Invest. 2015 Oct 1;125(10):3795-808. doi: 10.1172/JCI81979. Epub 2015 Aug 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Nuclear / metabolism
  • CRISPR-Cas Systems
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Cell Self Renewal / physiology*
  • Chromatin Assembly and Disassembly
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • Heterografts
  • Humans
  • Liver Neoplasms / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Multienzyme Complexes
  • Neoplasm Proteins / physiology*
  • Neoplastic Stem Cells / cytology*
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / physiology*
  • Octamer Transcription Factor-3 / physiology*
  • Protein Interaction Mapping
  • Retinoblastoma-Binding Protein 4 / metabolism
  • Signal Transduction
  • Spheroids, Cellular
  • Transcription Factors / deficiency
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*


  • Antigens, Nuclear
  • Multienzyme Complexes
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • RBBP4 protein, human
  • Retinoblastoma-Binding Protein 4
  • Transcription Factors
  • ZIC2 protein, human
  • fetal Alzheimer antigen