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Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation
The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway me...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265802/ https://www.ncbi.nlm.nih.gov/pubmed/30453531 http://dx.doi.org/10.3390/cancers10110449 |
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author | Ji, Xinyan Song, Lihua Sheng, Li Gao, Anhui Zhao, Yang Han, Shixun Zhang, Yuchao Zhu, Chu Zhao, Simeng Wang, Zhe Xu, Bohan Li, Li Li, Jia Tan, Ninghua Zhao, Bin |
author_facet | Ji, Xinyan Song, Lihua Sheng, Li Gao, Anhui Zhao, Yang Han, Shixun Zhang, Yuchao Zhu, Chu Zhao, Simeng Wang, Zhe Xu, Bohan Li, Li Li, Jia Tan, Ninghua Zhao, Bin |
author_sort | Ji, Xinyan |
collection | PubMed |
description | The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation. |
format | Online Article Text |
id | pubmed-6265802 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62658022018-12-03 Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation Ji, Xinyan Song, Lihua Sheng, Li Gao, Anhui Zhao, Yang Han, Shixun Zhang, Yuchao Zhu, Chu Zhao, Simeng Wang, Zhe Xu, Bohan Li, Li Li, Jia Tan, Ninghua Zhao, Bin Cancers (Basel) Article The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation. MDPI 2018-11-16 /pmc/articles/PMC6265802/ /pubmed/30453531 http://dx.doi.org/10.3390/cancers10110449 Text en © 2018 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 Ji, Xinyan Song, Lihua Sheng, Li Gao, Anhui Zhao, Yang Han, Shixun Zhang, Yuchao Zhu, Chu Zhao, Simeng Wang, Zhe Xu, Bohan Li, Li Li, Jia Tan, Ninghua Zhao, Bin Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation |
title | Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation |
title_full | Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation |
title_fullStr | Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation |
title_full_unstemmed | Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation |
title_short | Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation |
title_sort | cyclopeptide ra-v inhibits organ enlargement and tumorigenesis induced by yap activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265802/ https://www.ncbi.nlm.nih.gov/pubmed/30453531 http://dx.doi.org/10.3390/cancers10110449 |
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