Abstract
Previously, we have reported that Yes-associated protein (YAP) is upregulated in human glioma tissues and its level is positively correlated with patient prognosis. However, the role and mechanism of YAP in the highly invasive nature of human gliomas were largely unknown. In this study, examined by wound healing assay, transwell assay, or live-imaging, we found that YAP downregulation inhibited glioma cell migration and invasion, while YAP over-expression promoted them. Interestingly, the above effect of YAP on immortalized glioma cells was recapitulated in cultured primary glioma cells. In addition, the protein level of N-cadherin and Twist, two important proteins involved in tumor invasion, increased after YAP over-expression. Meanwhile, YAP over-expression significantly increased the F-actin level and changed the distribution of F-actin, leading to cytoskeletal reorganization, which plays an important role in cell motility. Furthermore, the promotion effect of YAP over-expression on glioma cell migration and invasion was partially abolished by Twist downregulation. Taken together, our findings show that YAP contributes to glioma cell migration and invasion by regulating N-cadherin and Twist, as well as cytoskeletal reorganization.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Artinian N, Cloninger C, Holmes B, Benavides-Serrato A, Bashir T, Gera J (2015) Phosphorylation of the Hippo pathway component AMOTL2 by the mTORC2 kinase promotes YAP signaling, resulting in enhanced glioblastoma growth and invasiveness. J Biol Chem 290(32):19387–19401. https://doi.org/10.1074/jbc.M115.656587
Cavallaro U, Christofori G (2004) Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4(2):118–132. https://doi.org/10.1038/nrc1276
Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D (2007) Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130(6):1120–1133. https://doi.org/10.1016/j.cell.2007.07.019
Edgar BA (2006) From cell structure to transcription: Hippo forges a new path. Cell 124(2):267–273. https://doi.org/10.1016/j.cell.2006.01.005
Espanel X, Sudol M (2001) Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains. J Biol Chem 276:14514–14523. https://doi.org/10.1074/jbc.M008568200
H C YX (2013) The role of LPA and YAP signaling in long-term migration of human ovarian cancer cells. Cell Commun Signal 11(1):31. https://doi.org/10.1186/1478-811X-11-31
Hergovich A (2012) YAP-Hippo signalling downstream of leukemia inhibitory factor receptor: implications for breast cancer. Breast Cancer Res : BCR 14(6):326. https://doi.org/10.1186/bcr3349
Howell M, Borchers C, Milgram SL (2004) Heterogeneous nuclear ribonuclear protein U associates with YAP and regulates its co-activation of Bax transcription. J Biol Chem 279(25):26300–26306. https://doi.org/10.1074/jbc.M401070200
Hsu YL, Hung JY, Chou SH, Huang MS, Tsai MJ, Lin YS, Chiang SY, Ho YW, Wu CY, Kuo PL (2015) Angiomotin decreases lung cancer progression by sequestering oncogenic YAP/TAZ and decreasing Cyr61 expression. Oncogene 34(31):4056–4068. https://doi.org/10.1038/onc.2014.333
Huang J, Wu S, Barrera J, Matthews K, Pan D (2005) The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell 122(3):421–434. https://doi.org/10.1016/j.cell.2005.06.007
Komuro A, Nagai M, Navin NE, Sudol M (2003) WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem 278(35):33334–33341. https://doi.org/10.1074/jbc.M305597200
Lacroix M et al (2001) A multivariate analysis of 416 patients with glioblastoma multiforme. J Neurosurg 95(2):190–198. https://doi.org/10.3171/jns.2001.95.2.0190
Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, A. Gray N, Zarate CA Jr, Charney DS (2003) Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 53(8):707–742. https://doi.org/10.1016/s0006-3223(03)00117-3
Modena P, Lualdi E, Facchinetti F, Veltman J, Reid JF, Minardi S, Janssen I, Giangaspero F, Forni M, Finocchiaro G, Genitori L, Giordano F, Riccardi R, Schoenmakers EFPM, Massimino M, Sozzi G (2006) Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J Clin Oncol : Off J Am Soc Clin Oncol 24(33):5223–5233. https://doi.org/10.1200/JCO.2006.06.3701
Nurnberg A, Kitzing T, Grosse R (2011) Nucleating actin for invasion. Nat Rev Cancer 11(3):177–187. https://doi.org/10.1038/nrc3003
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA (2006) Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A 103(33):12405–12410. https://doi.org/10.1073/pnas.0605579103
Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre J-Y (2012) Primary brain tumours in adults. Lancet 379(9830):1984–1996. https://doi.org/10.1016/s0140-6736(11)61346-9
RN J et al (2012) The Hippo pathway member Yap plays a key role in influencing fate decisions in muscle satellite cells. J Cell Sci 125(24):6009–6019. https://doi.org/10.1242/jcs.109546
SK Z et al (2004) Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J 2004:790–799. https://doi.org/10.1038/sj.emboj.7600073
Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D, Montgomery EA, Anders RA (2008) Expression of Yes-associated protein in common solid tumors. Hum Pathol 39(11):1582–1589. https://doi.org/10.1016/j.humpath.2008.04.012
Strano S, Monti O, Pediconi N, Baccarini A, Fontemaggi G, Lapi E, Mantovani F, Damalas A, Citro G, Sacchi A, del Sal G, Levrero M, Blandino G (2005) The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA damage. Mol Cell 18(4):447–459. https://doi.org/10.1016/j.molcel.2005.04.008
Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G (2001) Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem 276(18):15164–15173. https://doi.org/10.1074/jbc.M010484200
Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454. https://doi.org/10.1038/nrc822
Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60(3):166–193. https://doi.org/10.3322/caac.20069
Wada K, Itoga K, Okano T, Yonemura S, Sasaki H (2011) Hippo pathway regulation by cell morphology and stress fibers. Development 138(18):3907–3914. https://doi.org/10.1242/dev.070987
Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X (2010) Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci 101(5):1279–1285. https://doi.org/10.1111/j.1349-7006.2010.01511.x
Wang Y et al (2017) Beta-catenin-mediated YAP signaling promotes human glioma growth. J Exp Clin Cancer Res : CR 36:136. https://doi.org/10.1186/s13046-017-0606-1
Yagi R, Chen L-F, Shigesada K, Murakami Y, Ito Y (1999) A WW domain-containing Yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J 18(9):2551–2562. https://doi.org/10.1093/emboj/18.9.2551
Yang S et al (2015) Active YAP promotes pancreatic cancer cell motility, invasion and tumorigenesis in a mitotic phosphorylation-dependent manner through LPAR3. Oncotarget 6:36019–36031. https://doi.org/10.18632/oncotarget.5935
Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S, Lowe SW (2006) Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125(7):1253–1267. https://doi.org/10.1016/j.cell.2006.05.030
Zhang H, von Gise A, Liu Q, Hu T, Tian X, He L, Pu W, Huang X, He L, Cai CL, Camargo FD, Pu WT, Zhou B (2014) Yap1 is required for endothelial to mesenchymal transition of the atrioventricular cushion. J Biol Chem 289(27):18681–18692. https://doi.org/10.1074/jbc.M114.554584
Zhang L, Yang S, Chen X, Stauffer S, Yu F, Lele SM, Fu K, Datta K, Palermo N, Chen Y, Dong J (2015a) The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells. Mol Cell Biol 35(8):1350–1362. https://doi.org/10.1128/MCB.00102-15
Zhang X, Ding Z, Mo J, Sang B, Shi Q, Hu J, Xie S, Zhan W, Lu D, Yang M, Bian W, Zhou X, Yu R (2015b) GOLPH3 promotes glioblastoma cell migration and invasion via the mTOR-YB1 pathway in vitro. Mol Carcinog 54(11):1252–1263. https://doi.org/10.1002/mc.22197
Zhang H, Geng D, Gao J, Qi Y, Shi Y, Wang Y, Jiang Y, Zhang Y, Fu J, Dong Y, Gao S, Yu R, Zhou X et al (2016) Expression and significance of Hippo/YAP signaling in glioma progression tumour biology. J Int Soc Oncodev Biol Med 37(12):15665–15676. https://doi.org/10.1007/s13277-016-5318-1
Zhao B, Li L, Lei Q, Guan KL (2010) The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 24(9):862–874. https://doi.org/10.1101/gad.1909210
Zhao B, Li L, Wang L, Wang CY, Yu J, Guan KL (2012) Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 26(1):54–68. https://doi.org/10.1101/gad.173435.111
Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL (2007) Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21(21):2747–2761. https://doi.org/10.1101/gad.1602907
Acknowledgements
We thank Professor Chunmei Zhu in the School of International Education of Xuzhou Medical University for the English writing assistance.
Funding
This study was supported by National Natural Science Foundation of China (No. 81372699; No. 81672489; No.81472345) and the Six Major Talent Summit of Jiangsu Province (No. WSW-039).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Written informed consent was obtained from the patients and the study was approved by the ethics committee of the hospital.
Electronic supplementary material
Supplemental Figure 1
(GIF 99 kb)
Supplemental Figure 2
(GIF 193 kb)
Supplemental Figure 3
(GIF 79 kb)
Supplemental Figure 4
(GIF 78 kb)
(WMV 5622 kb)
(WMV 28129 kb)
(WMV 7955 kb)
(WMV 28804 kb)
Rights and permissions
About this article
Cite this article
Zhang, Y., Xie, P., Wang, X. et al. YAP Promotes Migration and Invasion of Human Glioma Cells. J Mol Neurosci 64, 262–272 (2018). https://doi.org/10.1007/s12031-017-1018-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-017-1018-6