ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells
Pingping Zhu, … , Jiayi Wu, Zusen Fan
Pingping Zhu, … , Jiayi Wu, Zusen Fan
Published August 31, 2015
Citation Information: J Clin Invest. 2015;125(10):3795-3808. https://doi.org/10.1172/JCI81979.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 1

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

Pingping Zhu, Yanying Wang, Lei He, Guanling Huang, Ying Du, Geng Zhang, Xinlong Yan, Pengyan Xia, Buqing Ye, Shuo Wang, Lu Hao, Jiayi Wu, Zusen Fan

×

Figure 8

The NURF complex is required for self-renewal of liver CSCs.

Options: View larger image (or click on image) Download as PowerPoint
The NURF complex is required for self-renewal of liver CSCs. (A) The NUR...
(A) The NURF complex enhances OCT4 expression. The NURF components were knocked down followed by detection of OCT4 expression. (B) Sphere formation was performed with NURF complex silenced primary cells. Six HCC samples obtained similar results. (C) Oncospheres generated by BPTF-, SNF2L-, and RBBP4-silenced primary cells were digested for gradient injection. Percentage of tumor-formation mice was calculated. (D) BPTF-deficient cells were established by a CRISPR/CAS9 system. BPTF deficiency was verified by Western blot. (E) BPTF KO cells were cultured for sphere-formation assays. Similar results were achieved in the tested 3 cell lines. (F) ChIP assays were performed using the indicated anti-NURF antibodies, and then OCT4 promoter enrichment regions were examined by quantitative RT-PCR. Scale bars: 500 μm (B and E). Data are shown as means ± SD. Two-tailed Student’s t test was used for statistical analysis. *P < 0.05 and **P < 0.01. Data are representative of at least 3 independent experiments.