YAP1-TEAD4-DKK1 is an effective target for inhibiting radiation resistance in esophageal squamous carcinoma and activation of the pathway may be related to poor prognosis of patients

Abstract

Abstract Background The resistance to radiationtherapy is responsible for the poor prognosis of ESCC(esophageal squamous cell carcinoma). Our previous clinical study confirmed that YAP1 gene amplification is one of the poor prognostic indicators of radical chemoradiotherapy for ESCC. However, the underlying mechanism by which YAP1 mediates radio-resistance still remained poorly understood. Here we aim to explore the combined guiding value and related action mechanism of YAP1 and its downstream target gene Dickkopf-related protein 1(DKK1) in the treatment of ESCC. Methods We collected the clinical information and tissues of 94 ESCC patients and histodochemistry and survival analysis were performed.Using Western, co-IP, CHIP and luciferase experiments to verify the expression and regulatory relationship of YAP1 and DKK1. We also performed cell viability, transwell, Immunofluorescence of γ-H2AX and clonogenic assay to investigate the proliferation capacity and radiation sensitivity of KYSE510 cells and KYSE150 cells after lentiviral-transfected cell lines were constructed. Finally, Tumor growth curves of mices were used to verify the relationship between cell viability and radiation sensitivity. Results Cell experiments demonstrated that YAP1 overexpression promoted the malignant phenotype of ESCC cells and DNA damage repair to mediate radioresistance. In our present study, YAP1 and DKK1 were firstly found to have a synergistic predictive value for ESCC prognosis. Both knockdown YAP1 and application of YAP1 inhibitor repressed transcriptional activation of DKK1. The CHIP experiment and luciferase reporter showed that YAP1 activated DKK1 directly through its transcription factor TEAD4, which both affected the proliferation and migration ability of esophageal cancer cells. Moreover, the application of the YAP1 inhibitor CA3 combined with X-rays could significantly suppressed the xenograft tumor formation. Conclusion In conclusion, our study uncovers the role and mechanisms through which YAP1 and DKK1 as key regulators of radiotherapy resitance. YAP1/TEAD4 directly regulated the expression of DKK1, both participated in cell radioresistance, proliferation, migration and invasion and may be a potential joint predictor of ESCC.