Abstract
Dickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5ʹ-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.
Highlights
Dickkopf1 (DKK1) was originally identified as an embryonic head inducer in Xenopus embryos and is a secreted protein that antagonizes Wnt signaling [1, 2]
We found that DKK1 signaling upregulates forkhead box M1 (FOXM1) expression and that FOXM1 acts as a transcription factor for DKK1 in pancreatic ductal adenocarcinoma (PDAC) and esophageal squamous cell carcinoma (ESCC) cells
We investigated whether FOXM1 induces DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. β-Catenin was primarily observed in the cytoplasm and nucleus of S2-CP8 and HPAF-II cells, which is the hallmark of Wnt signaling activation, whereas it was present in the plasma membrane of TE-5 and TE-8 cells (Supplementary Fig. S6A)
Summary
Dickkopf (DKK1) was originally identified as an embryonic head inducer in Xenopus embryos and is a secreted protein that antagonizes Wnt signaling [1, 2]. As a negative regulator of oncogenic Wnt signaling, DKK1 has been shown to inhibit the growth of various cancer cell lines in vitro and in vivo [2, 11, 13, 14], and DKK1 expression is restrained in some types of cancers due to DNA methylation, polycomb, and. The increase in DKK1 expression in cancer may be a result of aberrant activation of Wnt signaling [10]. We demonstrate that both proteins are frequently and simultaneously expressed in human PDAC and ESCC specimens These results offer new insight into the mechanism underlying DKK1 overexpression in cancer and suggest that DKK1 and FOXM1 create a positive feedback loop to stimulate cancer cell proliferation
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