Abstract
Ubiquitin C-terminal hydrolase-L1 (UCH-L1) catalyses the hydrolysis of ubiquitin ester and amide mainly in neuronal cells. Recently it was proposed as a marker with a potential role in carcinogenesis. However, the molecular mechanism underlying the biological function of UCH-L1 in tumor cells is poorly understood. We found that UCH-L1 is highly expressed in non-small lung cancer cell line H157, having high invasive potential, and that the expression of UCH-L1 in tumor cells enhances their invasive potential in vitro and in vivo. UCH-L1 changes cell morphology by regulating cell adhesion through Akt-mediated pathway. Suppressing UCH-L1 expression by RNAi significantly suppressed the invasion in vitro and in vivo, and the activation of Akt and downstream mitogen activated protein kinases c-Jun N-terminal kinases and p38, but not ERK. In Akt-negative mutants, overexpression of UCH-L1 does not affect the invasion and migration capability of H157 cells. These results suggest that UCH-L1 is a key molecule to regulate tumor-cell invasion by upstream activation of Akt.
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Bittencourt Rosas SL, Caballero OL, Dong SM, da Costa Carvalho Mda G, Sidransky D, Jen J . (2001). Methylation status in the promoter region of the human PGP9.5 gene in cancer and normal tissues. Cancer Lett 170: 73–79.
Brichory F, Beer D, Le Naour F, Giordano T, Hanash S . (2001). Proteomics-based identification of protein gene product 9.5 as a tumor antigen that induces a humoral immune response in lung cancer. Cancer Res 61: 7908–7912.
Caballero OL, Resto V, Patturajan M, Meerzaman D, Guo MZ, Engles J et al. (2002). Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1). Oncogene 21: 3003–3010.
Diebold BA, Fowler B, Lu J, Dinauer MC, Bokoch GM . (2004). Antagonistic cross-talk between Rac and Cdc42 GTPases regulates generation of reactive oxygen species. J Biol Chem 279: 28136–28142.
Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A et al. (2006). Ubiquitin hydrolase UCH-L1 rescues b-amyloid-induced decreases in synaptic function and contextual memory. Cell 126: 775–788.
Hibi K, Westra WH, Borges M, Goodman S, Sidransky D, Jen J . (1999). PGP9.5 as a candidate tumor marker for non-small-cell lung cancer. Am J Pathol 155: 711–715.
Honda K, Yamada T, Endo R, Ino Y, Gotoh M, Tsuda H et al. (1998). Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. J Cell Biol 140: 1383–1393.
Huang C, Jacobson K, Schaller MD . (2004). A role for JNK-paxillin signaling in cell migration. Cell Cycle 3: 4–6.
Kim YM, Seo J, Kim YH, Jeong J, Joo HJ, Lee DH et al. (2007). Systemic analysis of tyrosine phosphorylated proteins in angiopoietin-1 induced signaling pathway of endothelial cells. J Proteome Res 6: 3278–3290.
Kurisu S, Suetsugu S, Yamazaki D, Yamaguchi H, Takenawa T . (2005). Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells. Oncogene 24: 1309–1319.
Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury Jr PT . (2002). The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 111: 209–218.
Liu Y, Lashuel HA, Choi S, Xing X, Case A, Ni J et al. (2003). Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. Chem Biol 10: 837–846.
Lowe J, McDermott H, Landon M, Mayer RJ, Wilkinson KD . (1990). Ubiquitin carboxyl-terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases. J Pathol 161: 153–160.
Osaka H, Wang YL, Takada K, Takizawa S, Setsuie R, Li H et al. (2003). Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron. Hum Mol Genet 12: 1945–1958.
Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P et al. (1994). Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78: 59–66.
Reddy KB, Nabha SM, Atanaskova N . (2003). Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev 22: 395–403.
Saigoh K, Wang YL, Suh JG, Yamanishi T, Sakai Y, Kiyosawa H et al. (1999). Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nat Genet 23: 47–51.
Song EJ, Yim SH, Kim E, Kim NS, Lee KJ . (2005). Human Fas-associated factor 1, interacting with ubiquitinated proteins and valosin-containing protein, is involved in the ubiquitin-proteasome pathway. Mol Cell Biol 25: 2511–2524.
Tezel E, Hibi K, Nagasaka T, Nakao A . (2000). PGP9.5 as a prognostic factor in pancreatic cancer. Clin Cancer Res 6: 4764–4767.
Toyoshima H, Hunter T . (1994). p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78: 67–74.
Wojciak-Stothard B, Tsang LY, Haworth SG . (2005). Rac and Rho play opposing roles in the regulation of hypoxia/reoxygenation-induced permeability changes in pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol 288: L749–L760.
Yamana N, Arakawa Y, Nishino T, Kurokawa K, Tanji M, Itoh RE et al. (2006). The Rho-mDia1 pathway regulates cell polarity and focal adhesion turnover in migrating cells through mobilizing Apc and c-Src. Mol Cell Biol 26: 6844–6858.
Yamazaki T, Hibi K, Takase T, Tezel E, Nakayama H, Kasai Y et al. (2002). PGP9.5 as a marker for invasive colorectal cancer. Clin Cancer Res 8: 192–195.
Yoeli-Lerner M, Toker A . (2006). Akt/PKB signaling in cancer: a function in cell motility and invasion. Cell Cycle 5: 603–605.
Acknowledgements
This study was supported by SK Corp. Korea, KOSEF through the Center for Cell Signaling & Drug Discovery Research (CCS & DDR, R15-2006-002) at Ewha Womans University, by KOSEF Grant FPR05A2-480. Kim HJ, Nam YK, Kim YM, Kim HJ and Lim S were supported by the Brain Korea 21 project.
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Kim, H., Kim, Y., Lim, S. et al. Ubiquitin C-terminal hydrolase-L1 is a key regulator of tumor cell invasion and metastasis. Oncogene 28, 117–127 (2009). https://doi.org/10.1038/onc.2008.364
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DOI: https://doi.org/10.1038/onc.2008.364
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