title: YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression.
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.
authors.affiliation: 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].
authors.forename: Yijun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: 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].
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiangkun
authors.initials: X
authors.lastname: Han
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Fuming
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Xujun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Tong
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Yingyong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China.
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Kunliang
authors.initials: K
authors.lastname: Guan
authors.affiliation: Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D000091102:YAP-Signaling Proteins; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; C492363:ZEB2 protein, human; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases