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

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

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

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

Cancer Res. 2017 Nov 1;77(21):5769-5781. doi: 10.1158/0008-5472.CAN-17-0449. Epub 2017 Sep 15.

Authors

Hsinyi Huang^{1

2

3}, Wenjing Zhang^{4

2

3}, Yafang Pan^{1

2

3

5}, Yijun Gao^{1

2

3}, Lei Deng⁶, Fuming Li^{1

2

3}, Fei Li^{1

2

3}, Xueyan Ma^{1

2

3}, Shenda Hou^{1

2

3}, Jing Xu⁷, Peixue Li^{1

2

3}, Xiaoxun Li⁸, Guohong Hu⁸, Cheng Li⁹, Haiquan Chen¹⁰, Lei Zhang^{1

2

3

5}, Hongbin Ji^{4

2

3

5}

Affiliations

¹ State Key Laboratory of Cell Biology, Chinese Academy of Science, Shanghai, China.
² CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Science, Shanghai, China.
³ Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, China.
⁴ State Key Laboratory of Cell Biology, Chinese Academy of Science, Shanghai, China. [email protected] [email protected].
⁵ School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
⁶ Department of Bioinformatics, School of Life Science and Technology, Tong Ji University, Shanghai, China.
⁷ Department of Nephrology, Kidney Institute of CPLA, Changzheng Hospital, Second Military Medical University, Shanghai, China.
⁸ The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China.
⁹ Center for Bioinformatics, School of Life Science, Peking University, Beijing, China.
¹⁰ Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

PMID: 28916653
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.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Carcinoma, Squamous Cell / drug therapy
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Cell Line
Cell Line, Tumor
Digitoxin / pharmacology
Disease Progression
Down-Regulation / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Glutathione Peroxidase / genetics
Glutathione Peroxidase / metabolism*
HEK293 Cells
Humans
Immunoblotting
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Mice
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Phosphorylation
Reactive Oxygen Species / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Xenograft Model Antitumor Assays
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Phosphoproteins
Reactive Oxygen Species
TP63 protein, human
Transcription Factors
Tumor Suppressor Proteins
YAP-Signaling Proteins
YAP1 protein, human
Digitoxin
GPX2 protein, human
Glutathione Peroxidase