Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells

Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells

RUNX3 is a tumor suppressor for a variety of cancers. RUNX3 suppresses the canonical Wnt signaling pathway by binding to the TCF4/β-catenin complex, resulting in the inhibition of binding of the complex to the Wnt target gene promoter. Here, we confirmed that RUNX3 suppressed Wnt signaling activity...

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Main Authors: Ju, Xiaoli, Ishikawa, Tomo-o, Naka, Kazuhito, Ito, Kosei, Ito, Yoshiaki, Oshima, Masanobu
Format: Online
Language:English
Published: Blackwell Publishing Ltd 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317806/
id pubmed-4317806
recordtype oai_dc
spelling pubmed-43178062015-10-05 Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells Ju, Xiaoli Ishikawa, Tomo-o Naka, Kazuhito Ito, Kosei Ito, Yoshiaki Oshima, Masanobu Original Articles RUNX3 is a tumor suppressor for a variety of cancers. RUNX3 suppresses the canonical Wnt signaling pathway by binding to the TCF4/β-catenin complex, resulting in the inhibition of binding of the complex to the Wnt target gene promoter. Here, we confirmed that RUNX3 suppressed Wnt signaling activity in several gastric cancer cell lines; however, we found that RUNX3 increased the Wnt signaling activity in KatoIII and SNU668 gastric cancer cells. Notably, RUNX3 expression increased the ratio of the Wnt signaling-high population in the KatoIII cells. although the maximum Wnt activation level of individual cells was similar to that in the control. As found previously, RUNX3 also binds to TCF4 and β-catenin in KatoIII cells, suggesting that these molecules form a ternary complex. Moreover, the ChIP analyses revealed that TCF4, β-catenin and RUNX3 bind the promoter region of the Wnt target genes, Axin2 and c-Myc, and the occupancy of TCF4 and β-catenin in these promoter regions is increased by the RUNX3 expression. These results suggest that RUNX3 stabilizes the TCF4/β-catenin complex on the Wnt target gene promoter in KatoIII cells, leading to activation of Wnt signaling. Although RUNX3 increased the Wnt signaling activity, its expression resulted in suppression of tumorigenesis of KatoIII cells, indicating that RUNX3 plays a tumor-suppressing role in KatoIII cells through a Wnt-independent mechanism. These results indicate that RUNX3 can either suppress or activate the Wnt signaling pathway through its binding to the TCF4/β-catenin complex by cell context-dependent mechanisms. Blackwell Publishing Ltd 2014-04 2014-02-18 /pmc/articles/PMC4317806/ /pubmed/24447505 http://dx.doi.org/10.1111/cas.12356 Text en © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. http://creativecommons.org/licenses/by-nc/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Ju, Xiaoli
Ishikawa, Tomo-o
Naka, Kazuhito
Ito, Kosei
Ito, Yoshiaki
Oshima, Masanobu
spellingShingle Ju, Xiaoli
Ishikawa, Tomo-o
Naka, Kazuhito
Ito, Kosei
Ito, Yoshiaki
Oshima, Masanobu
Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells
author_facet Ju, Xiaoli
Ishikawa, Tomo-o
Naka, Kazuhito
Ito, Kosei
Ito, Yoshiaki
Oshima, Masanobu
author_sort Ju, Xiaoli
title Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells
title_short Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells
title_full Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells
title_fullStr Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells
title_full_unstemmed Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells
title_sort context-dependent activation of wnt signaling by tumor suppressor runx3 in gastric cancer cells
description RUNX3 is a tumor suppressor for a variety of cancers. RUNX3 suppresses the canonical Wnt signaling pathway by binding to the TCF4/β-catenin complex, resulting in the inhibition of binding of the complex to the Wnt target gene promoter. Here, we confirmed that RUNX3 suppressed Wnt signaling activity in several gastric cancer cell lines; however, we found that RUNX3 increased the Wnt signaling activity in KatoIII and SNU668 gastric cancer cells. Notably, RUNX3 expression increased the ratio of the Wnt signaling-high population in the KatoIII cells. although the maximum Wnt activation level of individual cells was similar to that in the control. As found previously, RUNX3 also binds to TCF4 and β-catenin in KatoIII cells, suggesting that these molecules form a ternary complex. Moreover, the ChIP analyses revealed that TCF4, β-catenin and RUNX3 bind the promoter region of the Wnt target genes, Axin2 and c-Myc, and the occupancy of TCF4 and β-catenin in these promoter regions is increased by the RUNX3 expression. These results suggest that RUNX3 stabilizes the TCF4/β-catenin complex on the Wnt target gene promoter in KatoIII cells, leading to activation of Wnt signaling. Although RUNX3 increased the Wnt signaling activity, its expression resulted in suppression of tumorigenesis of KatoIII cells, indicating that RUNX3 plays a tumor-suppressing role in KatoIII cells through a Wnt-independent mechanism. These results indicate that RUNX3 can either suppress or activate the Wnt signaling pathway through its binding to the TCF4/β-catenin complex by cell context-dependent mechanisms.
publisher Blackwell Publishing Ltd
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317806/
_version_ 1613184411443920896

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