Angiomotin-p130 inhibits β-catenin stability by competing with Axin for binding to tankyrase in breast cancer

Abstract

Growing evidence indicates that Angiomotin (Amot)-p130 and Amot-p80 have different physiological functions. We hypothesized that Amot-p130 is a tumor suppressor gene in breast cancer, in contrast with the canonical oncogenicity of Amot-p80 or total Amot. To clarify the role of Amot-p130 in breast cancer, we performed real-time quantitative PCR, western blotting, flow cytometry, microarray, immunofluorescence, immunoprecipitation, and tumor sphere-formation assays in vitro, as well as tumorigenesis and limited-dilution analysis in vivo. In this study, we showed that Amot-p130 inhibited the proliferation, migration, and invasion of breast cancer cells. Interestingly, transcriptional profiles indicated that genes differentially expressed in response to Amot-p130 knockdown were mostly related to β-catenin signaling in MCF7 cells. More importantly, most of the downstream partners of β-catenin were associated with stemness. In a further validation, Amot-p130 inhibited the cancer stem cell potential of breast cancer cells both in vitro and in vivo. Mechanistically, Amot-p130 decreased β-catenin stability by competing with Axin for binding to tankyrase, leading to a further inhibition of the WNT pathway. In conclusions, Amot-p130 functions as a tumor suppressor gene in breast cancer, disrupting β-catenin stability by competing with Axin for binding to tankyrase. Amot-p130 was identified as a potential target for WNT pathway-targeted therapies in breast cancer.

Wnt Signaling in the Tumor Microenvironment

“…One of the hallmarks of CSCs is to sustain long telomeres through high expression of telomerase reverse transcriptase (TERT) [20]. β-catenin directly augments TERT expression through promoter binding [21].Recent studies showed that GSK3β, AXIN binding to tankyrase, and the SOX family transcription factors played key roles in the maintenance of CSC traits in breast cancers through the Wnt signaling pathway [22][23][24]. One target gene of Wnt is Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a bona fide marker of adult stem cells in the gastrointestinal tract that acts to enhance Wnt/β catenin signaling [25].…”

Yes-Associated Protein Is Required for ZO-1-Mediated Tight-Junction Integrity and Cell Migration in E-Cadherin-Restored AGS Gastric Cancer Cells

“…YAP interacts with β-catenin [ 24 ] and influences Wnt signaling activity positively or negatively [ 16 ]. ZO-1 promotes establishment of AJ structures by interacting with α-catenin and the actin cytoskeleton [ 41 ].…”

“…Beyond the classical barrier functions of TJ structures [ 20 ], downregulation of TJ proteins such as claudins, occludin, and ZO-1 reduces metastatic features, including cell migration [ 21 , 22 , 23 ]. Angiomotin (AMOT) family proteins interact with YAP and multiple components of TJs and AJs, such as β-catenin and ZO-1 [ 24 , 25 ]. The scaffolding functions of AMOT lead to sequestration of YAP to TJs, reducing nuclear YAP activity and maintaining TJ integrity and epithelial cell polarity [ 11 , 26 ].…”

AMOT suppresses tumor progression via regulating DNA damage response signaling in diffuse large B-cell lymphoma

“…Nevertheless, in epithelial ovarian cancer, prostate cancer, liver cancer, osteosarcoma, and sinonasal tumors, AMOT was overexpressed and promoted tumor cell proliferation or invasion [10,[20][21][22][23]. AMOT participated in the regulation of several signaling pathways, including Hippo, Wnt, ERK1/2, and VEGFR-2 pathways [12,[24][25][26][27][28][29]. However, the effect of AMOT in hematopoietic malignancies has not been reported.…”