β-Catenin nuclear localization positively feeds back on EGF/EGFR-attenuated AJAP1 expression in breast cancer

Abstract

Background Adherent junction associated protein 1 (AJAP1), a typical molecule of adherent junctions, has been found to be a tumor suppressor in many cancer types. Aberrant activation of β-catenin has been demonstrated to be associated with malignant biological properties of tumors including breast cancer. This study aimed to investigate the function and mechanism of AJAP1-mediated β-catenin activity of breast cancer lines in vitro and in breast cancer patients. Methods AJAP1 and β-catenin expressions in breast cancer tissues and cell lines were detected by immunohistochemistry, western blotting and qRT-PCR. The EGF/EGFR axis-mediated AJAP1 attenuated β-catenin nuclear location was measured by western blotting, immunofluorescence assay, co-immunoprecipitation, luciferase assay and ubiquitination assays. Furthermore, the function of AJAP1 and β-catenin regulated breast cancer progression was explored both in vivo and in vitro . Results It was found that AJAP1 had a high negative correlation with β-catenin nuclear expression and was a novel tumor suppressor in breast cancer. AJAP1 loss can mediate β-catenin accumulated in cytoplasm and then transferred it to the nucleus, activating β-catenin transcriptional activity and downstream genes. Additionally, β-catenin can reverse the invasion, proliferation ability and tumorigenicity of the depletion of AJAP1 caused both in vivo and in vitro. Besides, EGF/EGFR also involved in the process of AJAP1-depiction induced β-catenin transactivation to the nucleus. More importantly, EGFR depletion/AJAP1 knocked down promoted the progression of breast cancer by regulating the activity of β-catenin nuclear transactivation. Conclusion This study demonstrated that AJAP1 acted as a putative tumor suppressor while β-catenin nuclear localization positively fed back on EGF/EGFR-attenuated AJAP1 expression in breast cancer, which might be beneficial to develop new therapeutic targets for decreasing nuclear β-catenin-mediated malignancy in breast cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1252-6) contains supplementary material, which is available to authorized users.

Downregulation of TET1 Promotes Bladder Cancer Cell Proliferation and Invasion by Reducing DNA Hydroxymethylation of AJAP1

“…It was previously reported that AJAP1 loss can enhance β-catenin translocation into the nucleus to transactivate its downstream target gene (28). Once looking up the DEGs list, we did find several Wnt/β-catenin target genes, such as CD44 and fibronectin (Fn1), were downregulated in TET1-CD transfectants (Figure 5A).…”

Indonesian Ginger (Bangle) Extract Promotes Neurogenesis of Human Neural Stem Cells through WNT Pathway Activation

“…The most common downregulated genes in Bangle extract- and c -Banglene-treated hfNSCs included gastrulation brain homeobox 2 ( GBX2 ), a negative regulator of forebrain development [ 24 ], and adherens junctions associated protein 1 ( AJAP1 ), a negative regulator of Wnt signaling [ 25 ]. The downregulation of these genes was confirmed by qRT-PCR, although the statistically significant reduction of AJAP1 expression in c -Banglene was not observed in this assay ( Figure 2 D).…”

“…A recent study reported that AJAP1 functions as a negative regulator of WNT signaling through preventing nuclear translocation of β-catenin by anchoring to cell membrane in breast cancer cell [ 25 ]. Here, we observed the reduction of AJAP1 gene in Bangle extract-treated cells ( Figure 2 D).…”

TGF-β1 stimulates epithelial–mesenchymal transition and cancer-associated myoepithelial cell during the progression from in situ to invasive breast cancer

“…Immunofluorescence assay was carried out as previously described [17]. CD10 (Bioss, China) CK8/18 (Thermo Fisher) were utilized for study.…”