Identification of beta-cetenin/TCF4 target genes in LS174T colorectal cancer cells using gene expression arrays

Aberrant activation of WNT signaling 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 tumor stem cell phenotype and identify the zinc-finger transcription factor GATA6 as key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells while it restricts BMP signaling to differentiated tumor cells. Genetic deletion of Gata6 in mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumor stem cells. In human tumors, GATA6 competes with beta-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been previously linked to increased susceptibility to develop CRC. Hence, GATA6 creates a permissive environment for tumor stem cell expansion by controlling the major signaling pathways that influence CRC initiation.

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Whissell G, Montagni E, Martinelli P, Hernando-Momblona X, Sevillano M, Jung P, Cortina C, Calon A, Abuli A, Castells A, Castellvi-Bel S, Nacht AS, Sancho E, Stephan-Otto Attolini C, Vicent GP, Real FX, Batlle E