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YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma

1
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
2
Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
3
Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 11490, Taiwan
4
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 661; https://doi.org/10.3390/cancers11050661
Received: 25 March 2019 / Revised: 3 May 2019 / Accepted: 7 May 2019 / Published: 13 May 2019
(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)
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Abstract

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. View Full-Text
Keywords: hepatocellular carcinoma; YC-1; β-catenin/TCF; ErbB3 binding protein 1 (EBP1); p42 isoform hepatocellular carcinoma; YC-1; β-catenin/TCF; ErbB3 binding protein 1 (EBP1); p42 isoform
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Wu, J.-Y.; Shih, Y.-L.; Lin, S.-P.; Hsieh, T.-Y.; Lin, Y.-W. YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma. Cancers 2019, 11, 661.

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