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

被引:105
作者
Gao, Yijun [1 ]
Zhang, Wenjing [1 ]
Han, Xiangkun [1 ]
Li, Fuming [1 ]
Wang, Xujun [2 ]
Wang, Rui [3 ]
Fang, Zhaoyuan [1 ]
Tong, Xinyuan [1 ]
Yao, Shun [1 ]
Li, Fei [1 ]
Feng, Yan [1 ]
Sun, Yihua [3 ]
Hou, Yingyong [4 ]
Yang, Zhongzhou [5 ]
Guan, Kunliang [6 ]
Chen, Haiquan [3 ]
Zhang, Lei [1 ]
Ji, Hongbin [1 ]
机构
[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200031, Peoples R China
[2] Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai 200092, Peoples R China
[3] Fudan Univ, Shanghai Canc Ctr, Dept Thorac Surg, Shanghai 200032, Peoples R China
[4] Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai 200032, Peoples R China
[5] Nanjing Univ, Model Anim Res Ctr, MOE Key Lab Model Anim Dis Study, Nanjing 210061, Jiangsu, Peoples R China
[6] Univ Calif San Diego, Moores Canc Ctr, Dept Pharmacol, La Jolla, CA 92093 USA
来源
NATURE COMMUNICATIONS | 2014年 / 5卷
基金
中国博士后科学基金; 中国国家自然科学基金;
关键词
YES-ASSOCIATED PROTEIN; TUMOR-SUPPRESSOR PATHWAY; STEM-LIKE CELLS; HIPPO PATHWAY; ADENOSQUAMOUS CARCINOMA; HEPATOCELLULAR-CARCINOMA; SIZE-CONTROL; ORGAN SIZE; CANCER; DIFFERENTIATION;
D O I
10.1038/ncomms5629
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页数:13
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