Abstract
E-cadherin is a cell–cell adhesion molecule that acts as a suppressor of cancer cell invasion and its expression is downregulated in many advanced, poorly differentiated, human cancers. In this study, we found that the expression of DLC1 (deleted in liver cancer 1) tumor-suppressor gene in metastatic prostate carcinoma (PCA) cells increased the expression of E-cadherin and resulted in an elevated rate of cell–cell aggregation as measured by aggregation assay. DLC1-mediated increase in E-cadherin expression was not dependent on α-catenin, a DLC1-binding protein associated with E-cadherin, and/or cellular density. The increase of E-cadherin expression occurred at mRNA level and relied on DLC1 RhoGAP function, leading to suppression of high level of RhoA-GTP and RhoC-GTP activity in metastatic PCA cells. Application of Rho/ROCK inhibitors produced the same effect as introduction of DLC1. Knocking down of RhoA produced a moderate increase in E-cadherin whereas knocking down of RhoC resulted in a significant increase of E-cadherin. Downregulation of E-cadherin caused by constitutively active RhoAV14 and RhoCV14 could not be reversed by expression of DLC1 in DLC1-negative cell line. DLC1-mediated suppression of metastatic PCA cells invasion was comparable with the one associated with ectopic E-cadherin expression, or caused by suppression of Rho pathway either by Rho/ROCK inhibitors, or by shRNA repression. This study demonstrates that DLC1 expression positively regulates E-cadherin and suppresses highly metastatic PCA cell invasion by modulating Rho pathway, which appears as a feasible therapeutic target in cancers with high activity of RhoGTPases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Goodison S, Yuan J, Sloan D, Kim R, Li C, Popescu NC et al. The RhoGAP protein DLC-1 functions as a metastasis suppressor in breast cancer cells. Cancer Res 2005; 65: 6042–6053.
Durkin ME, Yuan BZ, Zhou X, Zimonjic DB, Lowy DR, Thorgeirsson SS et al. DLC-1:a Rho GTPase-activating protein and tumour suppressor. J Cell Mol Med 2007; 11: 1185–1207.
Xue W, Krasnitz A, Lucito R, Sordella R, Vanaelst L, Cordon-Cardo C et al. DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma. Genes Dev 2008; 22: 1439–1444.
Vigil D, Cherfils J, Rossman KL, Der CJ . Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 2010; 12: 842–857.
Thiolloy S, Rinker-Schaeffer CW . Thinking outside the box: using metastasis suppressors as molecular tools. Semin Cancer Biol 2011; 21: 89–98.
Zhou X, Thorgeirsson SS, Popescu NC . Restoration of DLC-1 gene expression induces apoptosis and inhibits both cell growth and tumorigenicity in human hepatocellular carcinoma cells. Oncogene 2004; 23: 1308–1313.
Guan M, Tripathi V, Zhou X, Popescu NC . Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy. Cancer Gene Ther 2008; 15: 371–381.
Healy KD, Hodgson L, Kim TY, Shutes A, Maddileti S, Juliano RL et al. DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms. Mol Carcinog 2008; 47: 326–337.
Tripathi V, Popescu NC, Zimonjic DB . DLC1 interaction with α-catenin stabilizes adherens junctions and enhances DLC1 antioncogenic activity. Mol Cell Biol 2012; 32: 2145–2159.
Yam JW, Ko FC, Chan CY, Jin DY, Ng IO . Interaction of deleted in liver cancer 1 with tensin2 in caveolae and implications in tumor suppression. Cancer Res 2006; 66: 8367–8372.
Liao YC, Si L, deVere White RW, Lo SH . The phosphotyrosine-independent interaction of DLC-1 and the SH2 domain of cten regulates focal adhesion localization and growth suppression activity of DLC-1. J Cell Biol 2007; 176: 43–49.
Qian X, Li G, Asmussen HK, Asnaghi L, Vass WC, Braverman R et al. Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities. Proc Natl Acad Sci USA 2007; 104: 9012–9017.
Li G, Du X, Vass WC, Papageorge AG, Lowy DR, Qian X . Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK). Proc Natl Acad Sci USA 2011; 108: 17129–17134.
Sahai E, Marshall CJ . RHO-GTPases and cancer. Nat Rev Cancer 2002; 2: 133–142.
Fukata M, Kaibuchi K . Rho-family GTPases in cadherin-mediated cell-cell adhesion. Nat Rev Mol Cell Biol 2001; 2: 887–897.
Mège RM, Gavard J, Lambert M . Regulation of cell-cell junctions by the cytoskeleton. Curr Opin Cell Biol 2006; 18: 541–548.
Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000; 2: 84–89.
Li LC, Zhao H, Nakajima K, Oh BR, Ribeiro Filho LA et al. Methylation of the E-cadherin gene promoter correlates with progression of prostate cancer. J Urol 2001; 166: 705–709.
Hajra KM, Chen DY, Fearon ER . The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 2002; 62: 1613–1618.
Brouxhon S, Kyrkanides S, O’Banion MK, Johnson R, Pearce DA, Centola GM et al. Sequential down-regulation of E-cadherin with squamous cell carcinoma progression: loss of E-cadherin via a prostaglandin E2-EP2 dependent posttranslational mechanism. Cancer Res 2007; 67: 7654–7664.
Rashid MG, Sanda MG, Vallorosi CJ, Rios-Doria J, Rubin MA, Day ML . Posttranslational truncation and inactivation of human E-cadherin distinguishes prostate cancer from matched normal prostate. Cancer Res 2001; 61: 489–492.
Mosesson Y, Mills GB, Yarden Y . Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer 2008; 8: 835–850.
Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G . A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 1998; 392: 190–193.
Asnaghi L, Vass WC, Quadri R, Day PM, Qian X, Braverman R et al. E-cadherin negatively regulates neoplastic growth in non-small cell lung cancer: role of Rho GTPases. Oncogene 2010; 29: 2760–2771.
Guan M, Zhou X, Soulitzis N, Spandidos DA, Popescu NC . Aberrant methylation and deacetylation of deleted in liver cancer-1 gene in prostate cancer: potential clinical applications. Clin Cancer Res 2006; 12: 1412–1419.
Vleminckx K, Vakaet L, Mareel M, Fiers W, van Roy F . Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991; 66: 107–119.
Christofori G, Semb H . The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 1999; 24: 73–76.
Noren NK, Liu BP, Burridge K, Kreft B . p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J Cell Biol 2000; 150: 567–580.
Noë V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 2001; 114: 111–118.
Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A et al. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 1991; 113: 173–185.
Wong AS, Gumbiner BM . Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol 2003; 161: 1191–1203.
Köksal IT, Ozcan F, Kiliçaslan I, Tefekli A . Expression of E-cadherin in prostate cancer in formalin-fixed, paraffin-embedded tissues: correlation with pathological features. Pathology 2002; 34: 233–238.
Cheng L, Nagabhushan M, Pretlow TP, Amini SB, Pretlow TG . Expression of E-cadherin in primary and metastatic prostate cancer. Am J Pathol 1996; 148: 1375–1380.
Conacci-Sorrell M, Simcha I, Ben-Yedidia T, Blechman J, Savagner P, Ben-Ze’ev A . Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J Cell Biol 2003; 163: 847–857.
Lozano E, Bretson M, Braga VM . Tumor progression: small GTPases and loss of cell-cell adhesion. BioEssays 2003; 25: 452–463.
Braga VM, Yap AS . The challenges of abundance: epithelial junctions and small GTPase signalling. Curr Opin Cell Biol 2005; 17: 466–474.
Etienne-Manneville S, Hall A . Rho GTPases in cell biology. Nature 2002; 420: 629–635.
Vega FM, Ridley AJ . Rho GTPases in cancer cell biology. FEBS Lett 2008; 582: 2093–2101.
Hodge JC, Bub J, Kaul S, Kajdacsy-Balla A, Lindholm PF . Requirement of RhoA activity for increased nuclear factor kappaB activity and PC-3 human prostate cancer cell invasion. Cancer Res 2003; 63: 1359–1364.
Burbelo P, Wellstein A, Pestell RG . Altered Rho GTPasesignaling pathways in breast cancer cells. Breast Cancer Res Treat 2004; 84: 43–48.
Chang YW, Marlin JW, Chance TW, Jakobi R . RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cell motility. Cancer Res 2006; 66: 11700–11708.
Suwa H, Ohshio G, Imamura T, Watanabe G, Arii S, Imamura M et al. Overexpression ofthe RHOC gene correlates with progression of ductal adenocarcinomaof the pancreas. Br J Cancer 1998; 77: 147–152.
Clark EA, Golub TR, Lander ES, Hynes RO . Genomic analysis of metastasis reveals an essential role for RHOC. Nature 2000; 406: 532–535.
Wu M, Wu ZF, Rosenthal DT, Rhee EM, Merajver SD . Characterization of the roles of RHOC and RHOA GTPases in invasion, motility, and matrix adhesion in inflammatory and aggressive breast cancers. Cancer 2010; 116: 2768–2782.
Sequeira L, Dubyk CW, Riesenberger TA, Cooper CR, van Golen KL . Rho GTPases in PC-3 prostate cancer cell morphology, invasion and tumor cell diapedesis. Clin Exp Metastasis 2008; 25: 569–579.
Sahai E, Marshall CJ . ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol 2002; 4: 408–415.
Wong CC, Wong CM, Ko FC, Chan LK, Ching YP, Yam JW et al. Deleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma. PLoS One 2008; 3: e2779.
Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y et al. Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res 2003; 9: 2632–2641.
Sawada K, Morishige K, Mabuchi S, Ogata S, Kawase C, Sakata M et al. In vitro and in vivo assays to analyze the contribution of Rho kinase in angiogenesis. Methods Enzymol 2008; 439: 395–412.
Jeong KJ, Park SY, Cho KH, Sohn JS, Lee J, Kim YK et al. The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion. Oncogene 2012; 31: 4279–4289.
Sawada K, Mitra AK, Radjabi AR, Bhaskar V, Kistner EO, Tretiakova M et al. Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target. Cancer Res 2008; 68: 2329–2339.
Zhou Q, Yan B, Hu X, Li XB, Zhang J, Fang J . Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin. Mol Cancer Ther 2009; 8: 1684–1691.
Jiang WG, Hiscox S, Hallett MB, Horrobin DF, Mansel RE, Puntis MC . Regulation of the expression of E-cadherin on human cancer cells by gamma-linolenic acid (GLA). Cancer Res 1995; 55: 5043–5048.
Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 1997; 137: 231–245.
Annicotte JS, Iankova I, Miard S, Fritz V, Sarruf D, Abella A et al. Peroxisome proliferator-activated receptor gamma regulates E-cadherin expression and inhibits growth and invasion of prostate cancer. Mol Cell Biol 2006; 26: 7561–7574.
Lahoz A, Hall A . DLC1: a significant GAP in the cancer genome. Genes Dev 2008; 22: 1724–1730.
Zimonjic DB, Popescu NC . Role of DLC1 tumor suppressor gene and MYC oncogene in pathogenesis of human hepatocellular carcinoma: Potential prospects for combined targeted therapeutics. Int J Oncol 2012; 41: 393–406.
Acknowledgements
This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Tripathi, V., Popescu, N. & Zimonjic, D. DLC1 induces expression of E-cadherin in prostate cancer cells through Rho pathway and suppresses invasion. Oncogene 33, 724–733 (2014). https://doi.org/10.1038/onc.2013.7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2013.7
Keywords
This article is cited by
-
Evaluation of the causal relationship between smoking and schizophrenia in East Asia
Schizophrenia (2022)
-
Role of RhoC in cancer cell migration
Cancer Cell International (2021)
-
Mutational drivers of cancer cell migration and invasion
British Journal of Cancer (2021)
-
Nuclear DLC1 exerts oncogenic function through association with FOXK1 for cooperative activation of MMP9 expression in melanoma
Oncogene (2020)
-
The tumor suppressor DLC1 inhibits cancer progression and oncogenic autophagy in hepatocellular carcinoma
Laboratory Investigation (2018)