title: YAP promotes malignant progression of Lkb1-deficient lung adenocarcinoma through downstream regulation of survivin.
abstract: The serine/threonine kinase LKB1 is a well-characterized tumor suppressor that governs diverse cellular processes, including growth, polarity, and metabolism. Somatic-inactivating mutations in LKB1 are observed in about 15% to 30% of non-small cell lung cancers (NSCLC). LKB1 inactivation confers lung adenocarcinomas (ADC) with malignant features that remain refractory to therapeutic intervention. YAP activation has been linked to LKB1 deficiency, but the role of YAP in lung ADC formation and progression is uncertain. In this study, we showed that ectopic expression of YAP in type II alveolar epithelial cells led to hyperplasia in mouse lungs. YAP overexpression in the Kras(G12D) lung cancer mouse model accelerated lung ADC progression. Conversely, YAP deletion dramatically delayed the progression of lung ADC in LKB1-deficient Kras(G12D) mice. Mechanistic studies identified the antiapoptotic oncoprotein survivin as the downstream mediator of YAP responsible for promoting malignant progression of LKB1-deficient lung ADC. Collectively, our findings identify YAP as an important contributor to lung cancer progression, rationalizing YAP inhibition in the context of LKB1 deficiency as a therapeutic strategy to treat lung ADC.
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Fuming
authors.initials: F
authors.lastname: Li
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Tong
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xiangkun
authors.initials: X
authors.lastname: Han
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Long
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Life Science Institute, Zhejiang University, Hangzhou, China.
authors.forename: Hengyu
authors.initials: H
authors.lastname: Fan
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. hbji@sibcb.ac.cn.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
mesh_terms: D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018450:Disease Progression; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D000077022:Survivin; D014183:Transplantation, Heterologous; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C117749:Birc5 protein, mouse; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D000077022:Survivin; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)