Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma

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.

YAP1-NUTM1 Gene Fusion in Porocarcinoma of the External Auditory Canal

“…The tumorigenic effect of YAP1 has been verified in recent studies [15]. Therapeutic opportunities targeting the YAP1/ TEAD-dependent transcription are being tested in different neoplasms [16].…”

Clinical significance of YAP1 and TAZ in esophageal squamous cell carcinoma

“…Once YAP1 and TAZ are released, MST1/2 and LATS1/2 become deactivated, YAP1 and TAZ are dephosphorylated, and then they translocate into the nucleus to bind to TEADs to promote tumor development. [ 12 , 13 ]…”

Comprehensive Analysis of the Expression of TGF-β Signaling Regulators and Prognosis in Human Esophageal Cancer

“…For example, the Hippo coactivator YAP1 mediates EGFR overexpression and confers chemoresistance in EC [ 37 ]. Targeting the Hippo coactivator YAP1 through BET bromodomain inhibition could suppress EC growth [ 38 ]. Of note, various studies had indicated that TGF- β signaling was cross talked with these signalings in human cancers.…”