YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

Yijun Gao; Wenjing Zhang; Xiangkun Han; Fuming Li; Xujun Wang; Rui Wang; Zhaoyuan Fang; Xinyuan Tong; Shun Yao; Fei Li; Yan Feng; Yihua Sun; Yingyong Hou; Zhongzhou Yang; Kunliang Guan; Haiquan Chen; Lei Zhang; Hongbin Ji

doi:10.1038/ncomms5629

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

Nat Commun. 2014 Aug 13:5:4629. doi: 10.1038/ncomms5629.

Authors

Yijun Gao¹, Wenjing Zhang¹, Xiangkun Han², Fuming Li², Xujun Wang³, Rui Wang⁴, Zhaoyuan Fang², Xinyuan Tong², Shun Yao², Fei Li², Yan Feng², Yihua Sun⁴, Yingyong Hou⁵, Zhongzhou Yang⁶, Kunliang Guan⁷, Haiquan Chen⁴, Lei Zhang², Hongbin Ji²

Affiliations

¹ 1] State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China [2].
² State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
³ Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
⁴ Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁵ Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁶ MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China.
⁷ Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.

PMID: 25115923
DOI: 10.1038/ncomms5629

Abstract

Whether the Hippo pathway contributes to cell lineage transition under pathological conditions, especially tumorigenesis, remains largely unknown. Here we show that YAP, the major effector of the Hippo pathway, displays a distinct activation pattern in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC); YAP is initially activated by LKB1 loss in lung ADC, which upregulates ZEB2 expression and represses DNp63 transcription in a default manner. During transdifferentiation, YAP is inactivated, which in turn relieves ZEB2-mediated default repression of DNp63 and triggers squamous differentiation reprogramming. Disruption of the YAP barrier for phenotypic transition significantly accelerates squamous transdifferentiation, whereas constitutive YAP activation conversely inhibits this transition. More importantly, ectopic DNp63 expression rescues the inhibitory effect of YAP on squamous transdifferentiation. These findings have established YAP as an essential barrier for lung cancer cell fate conversion and provided a mechanism for regulating cancer plasticity, which might hold important implication for YAP-targeted therapies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / physiology*
Adenocarcinoma / genetics*
Adenocarcinoma / pathology
Adenocarcinoma / physiopathology
Animals
Carcinoma, Squamous Cell / genetics*
Carcinoma, Squamous Cell / pathology
Carcinoma, Squamous Cell / physiopathology
Cell Cycle Proteins
Cell Line, Tumor
Cell Transdifferentiation / genetics
Cell Transdifferentiation / physiology*
Disease Models, Animal
Down-Regulation / physiology
Female
Homeodomain Proteins / genetics
Homeodomain Proteins / physiology
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Lung Neoplasms / physiopathology
Male
Mice
Mice, Transgenic
Middle Aged
Phosphoproteins / genetics
Phosphoproteins / physiology*
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics
Repressor Proteins / genetics
Repressor Proteins / physiology
Trans-Activators / genetics
Trans-Activators / physiology
Transcription Factors / genetics
Transcription Factors / physiology
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / physiology
Up-Regulation / physiology
YAP-Signaling Proteins
Zinc Finger E-box Binding Homeobox 2

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Homeodomain Proteins
Phosphoproteins
Repressor Proteins
TP63 protein, human
Trans-Activators
Transcription Factors
Trp63 protein, mouse
Tumor Suppressor Proteins
YAP-Signaling Proteins
YAP1 protein, human
Yap1 protein, mouse
ZEB2 protein, human
ZEB2 protein, mouse
Zinc Finger E-box Binding Homeobox 2
Protein Serine-Threonine Kinases
STK11 protein, human
Stk11 protein, mouse
AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases