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Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma

Hippo/YAP1 signaling is a major regulator of organ size, cancer stemness, and aggressive phenotype. Thus, targeting YAP1 may provide a novel therapeutic strategy for tumors with high YAP1 expression in esophageal cancer (EC). Chromatin immunoprecipitation (ChiP) and quantitative ChiP‐PCR were used t...

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Autores principales: Song, Shumei, Li, Yuan, Xu, Yan, Ma, Lang, Pool Pizzi, Melissa, Jin, Jiankang, Scott, Ailing W, Huo, Longfei, Wang, Ying, Lee, Jeffrey H., Bhutani, Manoop S., Weston, Brian, Shanbhag, Namita D, Johnson, Randy L., Ajani, Jaffer A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266288/
https://www.ncbi.nlm.nih.gov/pubmed/32175692
http://dx.doi.org/10.1002/1878-0261.12667
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author Song, Shumei
Li, Yuan
Xu, Yan
Ma, Lang
Pool Pizzi, Melissa
Jin, Jiankang
Scott, Ailing W
Huo, Longfei
Wang, Ying
Lee, Jeffrey H.
Bhutani, Manoop S.
Weston, Brian
Shanbhag, Namita D
Johnson, Randy L.
Ajani, Jaffer A.
author_facet Song, Shumei
Li, Yuan
Xu, Yan
Ma, Lang
Pool Pizzi, Melissa
Jin, Jiankang
Scott, Ailing W
Huo, Longfei
Wang, Ying
Lee, Jeffrey H.
Bhutani, Manoop S.
Weston, Brian
Shanbhag, Namita D
Johnson, Randy L.
Ajani, Jaffer A.
author_sort Song, Shumei
collection PubMed
description Hippo/YAP1 signaling is a major regulator of organ size, cancer stemness, and aggressive phenotype. Thus, targeting YAP1 may provide a novel therapeutic strategy for tumors with high YAP1 expression in esophageal cancer (EC). Chromatin immunoprecipitation (ChiP) and quantitative ChiP‐PCR were used to determine the regulation of the chromatin remodeling protein bromodomain‐containing protein 4 (BRD4) on YAP1. The role of the bromodomain and extraterminal motif (BET) inhibitor JQ1, an established BRD4 inhibitor, on inhibition of YAP1 in EC cells was dissected using western blot, immunofluorescence, qPCR, and transient transfection. The antitumor activities of BET inhibitor were further examined by variety of functional assays, cell proliferation (MTS), tumorsphere, and ALDH1+ labeling in vitro and in vivo. Here, we show that BRD4 regulates YAP1 expression and transcription. ChiP assays revealed that BRD4 directly occupies YAP1 promoter and that JQ1 robustly blocks BRD4 binding to the YAP1 promoter. Consequently, JQ1 strongly suppresses constitutive or induced YAP1 expression and transcription in EC cells and YAP1/Tead downstream transcriptional activity. Intriguingly, radiation‐resistant cells that acquire strong cancer stem cell traits and an aggressive phenotype can be effectively suppressed by JQ1 as assessed by cell proliferation, tumorsphere formation, and reduction in the ALDH1+ cells. Moreover, effects of JQ1 are synergistically amplified by the addition of docetaxel in vitro and in vivo. Our results demonstrate that BRD4 is a critical regulator of Hippo/YAP1 signaling and that BRD4 inhibitor JQ1 represents a new class of inhibitor of Hippo/YAP1 signaling, primarily targeting YAP1 high and therapy‐resistant cancer cells enriched with cancer stem cell properties.
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spelling pubmed-72662882020-06-03 Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma Song, Shumei Li, Yuan Xu, Yan Ma, Lang Pool Pizzi, Melissa Jin, Jiankang Scott, Ailing W Huo, Longfei Wang, Ying Lee, Jeffrey H. Bhutani, Manoop S. Weston, Brian Shanbhag, Namita D Johnson, Randy L. Ajani, Jaffer A. Mol Oncol Research Articles Hippo/YAP1 signaling is a major regulator of organ size, cancer stemness, and aggressive phenotype. Thus, targeting YAP1 may provide a novel therapeutic strategy for tumors with high YAP1 expression in esophageal cancer (EC). Chromatin immunoprecipitation (ChiP) and quantitative ChiP‐PCR were used to determine the regulation of the chromatin remodeling protein bromodomain‐containing protein 4 (BRD4) on YAP1. The role of the bromodomain and extraterminal motif (BET) inhibitor JQ1, an established BRD4 inhibitor, on inhibition of YAP1 in EC cells was dissected using western blot, immunofluorescence, qPCR, and transient transfection. The antitumor activities of BET inhibitor were further examined by variety of functional assays, cell proliferation (MTS), tumorsphere, and ALDH1+ labeling in vitro and in vivo. Here, we show that BRD4 regulates YAP1 expression and transcription. ChiP assays revealed that BRD4 directly occupies YAP1 promoter and that JQ1 robustly blocks BRD4 binding to the YAP1 promoter. Consequently, JQ1 strongly suppresses constitutive or induced YAP1 expression and transcription in EC cells and YAP1/Tead downstream transcriptional activity. Intriguingly, radiation‐resistant cells that acquire strong cancer stem cell traits and an aggressive phenotype can be effectively suppressed by JQ1 as assessed by cell proliferation, tumorsphere formation, and reduction in the ALDH1+ cells. Moreover, effects of JQ1 are synergistically amplified by the addition of docetaxel in vitro and in vivo. Our results demonstrate that BRD4 is a critical regulator of Hippo/YAP1 signaling and that BRD4 inhibitor JQ1 represents a new class of inhibitor of Hippo/YAP1 signaling, primarily targeting YAP1 high and therapy‐resistant cancer cells enriched with cancer stem cell properties. John Wiley and Sons Inc. 2020-04-07 2020-06 /pmc/articles/PMC7266288/ /pubmed/32175692 http://dx.doi.org/10.1002/1878-0261.12667 Text en © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Song, Shumei
Li, Yuan
Xu, Yan
Ma, Lang
Pool Pizzi, Melissa
Jin, Jiankang
Scott, Ailing W
Huo, Longfei
Wang, Ying
Lee, Jeffrey H.
Bhutani, Manoop S.
Weston, Brian
Shanbhag, Namita D
Johnson, Randy L.
Ajani, Jaffer A.
Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma
title Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma
title_full Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma
title_fullStr Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma
title_full_unstemmed Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma
title_short Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma
title_sort targeting hippo coactivator yap1 through bet bromodomain inhibition in esophageal adenocarcinoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266288/
https://www.ncbi.nlm.nih.gov/pubmed/32175692
http://dx.doi.org/10.1002/1878-0261.12667
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