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Title:
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GATA6 Activates Wnt Signaling in Pancreatic Cancer by Negatively Regulating the Wnt Antagonist Dickkopf-1
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Author:
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Zhong, Yi; Wang, Zheng; Fu, Baojin; Pan, Fan; Yachida, Shinichi; Dhara, Mousumi; Albesiano, Emilia; Li, Li; Naito, Yoshiki; Vilardell, Felip; Cummings, Christopher; Martinelli, Paola; Li, Ang; Yonescu, Raluca; Ma, Qingyong; Griffin, Constance A.; Real, Francisco X.; Iacobuzio-Donahue, Christine A.
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Notes:
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Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance.
Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways
have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic
carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation.
GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic
intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient
survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in
vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to
corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as
forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they
affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a
dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was
confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6,
but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into
culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells.
These findings illustrate that one mechanism by which GATA6 promotes pancreatic carcinogenesis is by virtue of its
activation of canonical Wnt signaling via regulation of DKK1. |
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Rights:
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cc-by, (c) Zhong et al., 2011
http://creativecommons.org/licenses/by/3.0/es/
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Document type:
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article
publishedVersion |
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Published by:
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Public Library of Science
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