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YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma
Novel drugs targeting Wnt signaling are gradually being developed for hepatocellular carcinoma (HCC) treatment. In this study, we used a Wnt-responsive Super-TOPflash (STF) luciferase reporter assay to screen a new compound targeting Wnt signaling. 3-(5′-Hydroxymethyl-2′-furyl)-1-benzylindazole (YC-...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562864/ https://www.ncbi.nlm.nih.gov/pubmed/31086087 http://dx.doi.org/10.3390/cancers11050661 |
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author | Wu, Ju-Yun Shih, Yu-Lueng Lin, Shih-Ping Hsieh, Tsai-Yuan Lin, Ya-Wen |
author_facet | Wu, Ju-Yun Shih, Yu-Lueng Lin, Shih-Ping Hsieh, Tsai-Yuan Lin, Ya-Wen |
author_sort | Wu, Ju-Yun |
collection | PubMed |
description | Novel drugs targeting Wnt signaling are gradually being developed for hepatocellular carcinoma (HCC) treatment. In this study, we used a Wnt-responsive Super-TOPflash (STF) luciferase reporter assay to screen a new compound targeting Wnt signaling. 3-(5′-Hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1) was identified as a small molecule inhibitor of the Wnt/β-catenin pathway. Our coimmunoprecipitation (co-IP) data showed that YC-1 did not affect the β-catenin/TCF interaction. Then, by mass spectrometry, we identified the ErbB3 receptor-binding protein 1 (EBP1) interaction with the β-catenin/TCF complex upon YC-1 treatment. EBP1 encodes two splice isoforms, p42 and p48. We further demonstrated that YC-1 enhances p42 isoform binding to the β-catenin/TCF complex and reduces the transcriptional activity of the complex. The suppression of colony formation by YC-1 was significantly reversed after knockdown of both isoforms (p48 and p42); however, the inhibition of colony formation was maintained when only EBP1 p48 was silenced. Taken together, these results suggest that YC-1 treatment results in a reduction in Wnt-regulated transcription through EBP1 p42 and leads to the inhibition of tumor cell proliferation. These data imply that YC-1 is a drug that antagonizes Wnt/β-catenin signaling in HCC. |
format | Online Article Text |
id | pubmed-6562864 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-65628642019-06-17 YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma Wu, Ju-Yun Shih, Yu-Lueng Lin, Shih-Ping Hsieh, Tsai-Yuan Lin, Ya-Wen Cancers (Basel) Article Novel drugs targeting Wnt signaling are gradually being developed for hepatocellular carcinoma (HCC) treatment. In this study, we used a Wnt-responsive Super-TOPflash (STF) luciferase reporter assay to screen a new compound targeting Wnt signaling. 3-(5′-Hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1) was identified as a small molecule inhibitor of the Wnt/β-catenin pathway. Our coimmunoprecipitation (co-IP) data showed that YC-1 did not affect the β-catenin/TCF interaction. Then, by mass spectrometry, we identified the ErbB3 receptor-binding protein 1 (EBP1) interaction with the β-catenin/TCF complex upon YC-1 treatment. EBP1 encodes two splice isoforms, p42 and p48. We further demonstrated that YC-1 enhances p42 isoform binding to the β-catenin/TCF complex and reduces the transcriptional activity of the complex. The suppression of colony formation by YC-1 was significantly reversed after knockdown of both isoforms (p48 and p42); however, the inhibition of colony formation was maintained when only EBP1 p48 was silenced. Taken together, these results suggest that YC-1 treatment results in a reduction in Wnt-regulated transcription through EBP1 p42 and leads to the inhibition of tumor cell proliferation. These data imply that YC-1 is a drug that antagonizes Wnt/β-catenin signaling in HCC. MDPI 2019-05-13 /pmc/articles/PMC6562864/ /pubmed/31086087 http://dx.doi.org/10.3390/cancers11050661 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wu, Ju-Yun Shih, Yu-Lueng Lin, Shih-Ping Hsieh, Tsai-Yuan Lin, Ya-Wen YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma |
title | YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma |
title_full | YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma |
title_fullStr | YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma |
title_full_unstemmed | YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma |
title_short | YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma |
title_sort | yc-1 antagonizes wnt/β-catenin signaling through the ebp1 p42 isoform in hepatocellular carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562864/ https://www.ncbi.nlm.nih.gov/pubmed/31086087 http://dx.doi.org/10.3390/cancers11050661 |
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