MBD3 inhibits formation of liver cancer stem cells

Oncotarget. 2017 Jan 24;8(4):6067-6078. doi: 10.18632/oncotarget.13496.

Abstract

Liver cancer cells can be reprogrammed into induced cancer stem cells (iCSCs) by exogenous expression of the reprogramming transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM). The nucleosome remodeling and deacetylase (NuRD) complex is essential for reprogramming somatic cells. In this study, we investigated the function of NuRD in the induction of liver CSCs. We showed that suppression of methyl-CpG binding domain protein 3 (MBD3), a core subunit of the NuRD repressor complex, together with OSKM transduction, induces conversion of liver cancer cells into stem-like cells. Expression of the transcription factor c-JUN is increased in MBD3-depleted iCSCs, and c-JUN activates endogenous pluripotent genes and regulates iCSC-related genes. These results indicate that MBD3/NuRD inhibits the induction of iCSCs, while c-JUN facilitates the generation of CSC-like properties. The iCSC reprogramming approach devised here provides a novel platform for dissection of the disordered signaling in liver CSCs. In addition, our results indicate that c-JUN may serve as a potential target for liver cancer therapy.

Keywords: C3A; MBD3/NuRD; c-JUN; induced liver cancer stem cells; transcriptional regulation.

MeSH terms

  • Cellular Reprogramming
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Hep G2 Cells
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Liver Neoplasms / metabolism*
  • Neoplastic Stem Cells / cytology*
  • Neoplastic Stem Cells / metabolism
  • Octamer Transcription Factor-3 / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • SOXB1 Transcription Factors / genetics

Substances

  • DNA-Binding Proteins
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • MBD3 protein, human
  • MYC protein, human
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins c-myc
  • SOX2 protein, human
  • SOXB1 Transcription Factors