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

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

Author information

1
Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
2
1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2].
3
1] Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain [2].
4
1] Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Catalonia, Spain [2] Department of Gastroenterology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Centre), Pompeu Fabra University, 08003 Barcelona, Catalonia, Spain.
5
Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Catalonia, Spain.
6
Centre de Regulació Genòmica (CRG), Universitat Pompeu Fabra (UPF), E-08003 Barcelona, Spain.
7
1] Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain [2] Universitat Pompeu Fabra, 08003 Barcelona, Spain.
8
1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.

Abstract

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.

PMID:
24952462
DOI:
10.1038/ncb2992
[Indexed for MEDLINE]

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