GATA6 Activates Wnt Signaling in Pancreatic Cancer by Negatively Regulating the Wnt Antagonist Dickkopf-1

Abstract

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.

Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3 , GATA6 , and TWIST1 in the Sezary Syndrome

“…Finally, TWIST1 can be directly targeted for upregulation by STAT3 (Qin et al, 2012), an important driver of CTCL pathogenesis . Similarly, overexpression of GATA6 has been implicated in oncogenesis by increasing the Wnt signaling pathway (Zhong et al, 2011). Finally, a recent study suggested that PLS3 overexpression confers anti-apoptotic properties to T cells along with an increase in their migration properties (Begue et al, 2012).…”

The emerging role of the TGFβ tumor suppressor pathway in pancreatic cancer

“…21 The TGFβ and HH/GLI pathway are coordinately expressed in many developmental processes. In pancreatic cancer, this normal regulation is disrupted by abnormal functioning of the TGFβ pathway, and GLI1 becomes a subverted downstream target of the oncogenic KRAS.…”

MicroRNA-143 inhibits tumorigenesis in hepatocellular carcinoma by downregulating GATA6

“…5). GATA6 is reported to be an oncogene in various cancers such as colon (18), pancreatic (19) or colorectal cancer (28), but the function of GATA6 in liver cancer is still elusive. The current study showed direct involvement of GATA6 in miR-143-mediated HCC regulation, suggesting that GATA6 also serves an oncogenic function in HCC, which may be related to miRNA dysregulation.…”

“…GATA-binding factor 6 (GATA6) has previously been described as a transcriptional factor with a zinc finger structure, which serves as an oncogenic factor in various types of tumor (17)(18)(19). For instance, it has been demonstrated that GATA6 can favor cancer progression by activating Wnt signaling in pancreatic cancer (17,19).…”

“…For instance, it has been demonstrated that GATA6 can favor cancer progression by activating Wnt signaling in pancreatic cancer (17,19). In addition, GATA6 is reported to induce metastasis of colorectal carcinomas, possibly through urokinase-type plasminogen activator expression in colon cancer (18).…”