Abstract
Lung cancer is one of the most devastating diseases worldwide with high incidence and mortality. Hippo (Hpo) pathway is a conserved regulator of organ size in both Drosophila and mammals. Emerging evidence has suggested the significance of Hpo pathway in cancer development. In this study, we identify VGLL4 as a novel tumor suppressor in lung carcinogenesis through negatively regulating the formation of YAP-TEAD complex, the core component of Hpo pathway. Our data show that VGLL4 is frequently observed to be lowly expressed in both mouse and human lung cancer specimens. Ectopic expression of VGLL4 significantly suppresses the growth of lung cancer cells in vitro. More importantly, VGLL4 significantly inhibits lung cancer progression in de novo mouse model. We further find that VGLL4 inhibits the activity of the YAP-TEAD transcriptional complex. Our data show that VGLL4 directly competes with YAP in binding to TEADs and executes its growth-inhibitory function through two TDU domains. Collectively, our study demonstrates that VGLL4 is a novel tumor suppressor for lung cancer through negatively regulating the YAP-TEAD complex formation and thus the Hpo pathway.
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11 August 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41422-021-00551-4
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Acknowledgements
We thank Drs T Jacks, R Depinho, K Wong for providing the KrasG12D, Lkb1L/L and p53L/L mice; Drs Kunliang Guan, Bin Zhao, Qunying Lei, Zengqiang Yuan for sharing reagents; Drs Dangsheng Li, Yun Zhao for invaluable comments on the manuscript and Drs Yan Ren, Zhaoyuan Fang, Bin Gao, Yihua Sun, Junhua Zhang for technical supports. This work was supported by Ministry of Science and Technology of China (2012CB910800, 2010CB912102, 2012CB945001), the Cross and Cooperation in Science and Technology Innovation Team program, the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01010406), the National Natural Science Foundation of China (31370747), Post-Doctor Research Program of Shanghai Institutes for Biological Sciences (2012KIP502, 2013KIP303, 2012KIP401), China Postdoctoral Science Foundation (2011M500826, 2013T60476), the Sanofi-Aventis Shanghai Institutes for Biological Sciences (SA-SIBS) scholarship program and KC Wong Education Foundation Scholarship. The authors gratefully acknowledge the support of SA-SIBS scholarship.
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Figure S1
Detection of VGLL4 expression in NSCLC cell lines (PDF 55 kb)
Supplementary information, Figure S2
Detection of VGLL4 expression in A549 and CRL5872 cells. (PDF 33 kb)
Supplementary information, Figure S3
Different levels of VGLL4 expression in lung tumors from KrasG12D, p53L/L/KrasG12D and Lkb1L/L/KrasG12D mouse models. (PDF 141 kb)
Supplementary information, Figure S4
Statistical analysis of the total number and area lung tumors from LKB1L/L/KrasG12D mice virally infected with Lenti-Ctrl-Cre or Lenti-VGLL4-Cre. (PDF 71 kb)
Supplementary information, Figure S5
Statistical analysis of low grade and high grade tumors from LKB1L/L/KrasG12D mice virally infected with Lenti-Ctrl-Cre or Lenti-VGLL4-Cre. (PDF 52 kb)
Supplementary information, Figure S6
The nuclear co-localization and interaction of VGLL4 and TEAD4. (PDF 74 kb)
Supplementary information, Figure S7
Inactivation of TEADs impairs VGLL4's suppressive role on lung cancer cell growth. (PDF 149 kb)
Supplementary information, Figure S8
Detection of VGLL4 widetype and mutant expression in A549 and CRL5872 cells. (PDF 127 kb)
Supplementary information, Figure S9
Detection of VGLL4 RNAi efficiency in HEK-293T cells. (PDF 29 kb)
Supplementary information, Figure S10
Detection of VGLL4 RNAi efficiency in Beas2B and CRL-5807 cells. (PDF 39 kb)
Supplementary information, Figure S11
Ectopic VGLL4 expression down-regulates the CTGF reporter gene activity enhanced by YAP expression. (PDF 49 kb)
Supplementary information, Figure S12
VGLL4 expression doesn't cause YAP degradation and nuclear exportation. (PDF 172 kb)
Supplementary information, Figure S13
Detection of YAP and VGLL4 expression in A549 cells. (PDF 25 kb)
Supplementary information, Figure S14
VGLL4 inhibits the growth of Hela and HepG2 cells. (PDF 62 kb)
Supplementary information, Figure S15
The second TDU domain is more important for VGLL4's suppressive role on lung cancer cell growth. (PDF 124 kb)
Supplementary information, Figure S16
VGLL1 promotes anchorage-independent growth of A549 cells. (PDF 64 kb)
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Zhang, W., Gao, Y., Li, P. et al. VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell Res 24, 331–343 (2014). https://doi.org/10.1038/cr.2014.10
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DOI: https://doi.org/10.1038/cr.2014.10
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