Embryonic NANOG activity defines colorectal cancer stem cells and modulates through AP1- and TCF-dependent mechanisms

Stem Cells. 2012 Oct;30(10):2076-87. doi: 10.1002/stem.1182.


Embryonic NANOG (NANOG1) is considered as an important regulator of pluripotency while NANOGP8 (NANOG-pseudogene) plays a role in tumorigenesis. Herein, we show NANOG is expressed from both NANOG1 and NANOGP8 in human colorectal cancers (CRC). Enforced NANOG1-expression increases clonogenic potential and tumor formation in xenograft models, although it is expressed only in a small subpopulation of tumor cells and is colocalized with endogenous nuclear β-catenin(High) . Moreover, single NANOG1-CRCs form spherical aggregates, similar to the embryoid body of embryonic stem cells (ESCs), and express higher levels of stem-like Wnt-associated target genes. Furthermore, we show that NANOG1-expression is positively regulated by c-JUN and β-catenin/TCF4. Ectopic expression of c-Jun in murine Apc(Min/+) -ESCs results in the development of larger xenograft tumors with higher cell density compared to controls. Chromatin immunoprecipitation assays demonstrate that c-JUN binds to the NANOG1-promoter via the octamer M1 DNA element. Collectively, our data suggest that β-Catenin/TCF4 and c-JUN together drive a subpopulation of CRC tumor cells that adopt a stem-like phenotype via the NANOG1-promoter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 1 / genetics
  • Adaptor Protein Complex 1 / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Binding Sites
  • Cell Transformation, Neoplastic
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Male
  • Mice
  • Nanog Homeobox Protein
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Promoter Regions, Genetic
  • Protein Binding
  • Pseudogenes
  • Signal Transduction / genetics
  • Transcription Factor 4
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • beta Catenin / genetics


  • Adaptor Protein Complex 1
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CTNNB1 protein, human
  • Homeodomain Proteins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • JNK Mitogen-Activated Protein Kinases