Abstract

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.

Highlights

  • Esophageal cancer (EC) is highly virulent and a major global health burden with more than 600 000 new cases each year (Torre et al, 2016)

  • We previously reported that yes-associated protein 1 (YAP1) plays an important role in maintaining EC cell growth, therapy resistance, and endowment of cancer stem cells (CSCs) properties (Song et al, 2014; Song et al, 2015)

  • To determine whether JQ1 suppresses YAP1 expression and transcription, several Esophageal adenocarcinoma (EAC) cell lines SKGT-4, BE3, Flo-1, JHESO, and OACP were treated with JQ1 at relative low concentration as indicated for 48 h, we found that JQ1 suppressed YAP1 and its target transcription factor SOX-9 (SOX9) expression in EAC cell lines (Fig. 1A)

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Summary

Introduction

Esophageal cancer (EC) is highly virulent and a major global health burden with more than 600 000 new cases each year (Torre et al, 2016). Esophageal adenocarcinoma (EAC), the predominant histology in the United States, has a rising incidence in the West (Brown et al, 2008; Torre et al, 2016). EAC is often diagnosed late based on symptoms, and cure rates are only 15% for all comers (Ajani et al, 2015). The. Abbreviations BET, the bromodomain and extraterminal protein; ChiP, chromatin immunoprecipitation; CSCs, cancer stem cells; EAC, esophageal adenocarcinoma; EC, esophageal cancer; ESCA, esophageal carcinoma; ESCC, esophageal squamous cell carcinoma; qPCR, quantitative real-time PCR; SOX9, transcription factor SOX-9; TCGA, The Cancer Genome Atlas; VP, verteporfin; YAP1, yes-associated protein 1. Molecular Oncology 14 (2020) 1410–1426 a 2020 The Authors.

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