The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression

Nat Cell Biol. 2014 Jul;16(7):695-707. doi: 10.1038/ncb2992. Epub 2014 Jun 22.


Aberrant activation of WNT signalling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumour stem cell phenotype and identify the zinc-finger transcription factor GATA6 as a key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells whereas it restricts BMP signalling to differentiated tumour cells. Genetic deletion of Gata6 from mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumour stem cells. In human tumours, GATA6 competes with β-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been linked to increased susceptibility to development of CRC. Hence, GATA6 creates an environment permissive for CRC initiation by lowering the threshold of BMP signalling required for tumour stem cell expansion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma* / pathology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Bone Morphogenetic Protein Receptors / genetics*
  • Bone Morphogenetic Protein Receptors / metabolism
  • Cell Proliferation
  • Colorectal Neoplasms / physiopathology*
  • Female
  • Fluorescent Antibody Technique
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism*
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • Male
  • Mice
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Stem Cells / metabolism*
  • Wnt Proteins / metabolism


  • Antineoplastic Agents
  • GATA6 Transcription Factor
  • LDN 193189
  • Pyrazoles
  • Pyrimidines
  • Wnt Proteins
  • Bone Morphogenetic Protein Receptors