YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63-GPX2 Axis and ROS Accumulation.

Hsinyi Huang,Shenda Hou,Fei Li,Yafang Pan,Lei Deng,Guohong Hu,Cheng Li,Xueyan Ma,Hongbin Ji,Lei Zhang,Peixue Li,Xiaoxun Li,Jing Xu,Wenjing Zhang,Fuming Li,Haiquan Chen,Yijun Gao

doi:10.1158/0008-5472.can-17-0449

Abstract

Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non-small cell lung cancer, is often refractory to therapy. Screening a small-molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor-suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC. Cancer Res; 77(21); 5769-81. ©2017 AACR.

Highlights

Lung cancer is the major health burden worldwide with high incidence and mortality [1]
We have revealed an unexpected role of YAP in the suppression of lung squamous cell carcinoma (SCC) growth through disruption of intracellular reactive oxygen species (ROS) homeostasis via the DNp63–GPX2 axis
Reactivation of YAP by digitoxin shows tumor growth inhibition potential in both human lung SCC cell xenograft and preclinical lung SCC Patient-derived xenograft (PDX) models. These data demonstrate that the novel tumor-suppressive function of YAP correlates with digitoxin treatment and provides potential therapeutic strategy for treatment of human lung SCC with low YAP expression

Summary

Introduction

Lung cancer is the major health burden worldwide with high incidence and mortality [1]. On the basis of the clinical and histological criteria, lung cancer can be classified into small-cell lung cancer (SCLC) and non–small cell lung cancer 2), and the latter is the most common subtype of lung cancer with a grim prognosis [3]. Lung squamous cell carcinoma (SCC) accounts for approximately 30% of NSCLC cases [2], which. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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Conclusion