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Deleted in Liver Cancer-1 (DLC1): An Emerging Metastasis Suppressor Gene

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Abstract

While significant progress continues to be made in the early detection and therapeutic management of primary tumors, the incidence of metastatic disease remains the major cause of mortality. Accordingly, the development of novel effective therapies that can ameliorate dissemination and secondary tumor growth are a clinical priority. The identification of genetic and functional alterations in cancer cells that affect factors implicated in the metastatic process is critical for designing preventive and therapeutic strategies. Evidence implicating the protein deleted in liver cancer-1 (DLC1), a Rho GTPase activator, in metastasis has accumulated to a point where DLC1 may be considered as a metastasis suppressor gene. This review presents evidence supporting an anti-metastatic role for DLC1 in several human cancers and discusses the mechanisms contributing to its inhibitory effects. In addition, promising opportunities for therapeutic interventions based on DLC1 function and downstream pathways involved in the metastatic process are considered.

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References

  1. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147(2):275–92. doi:10.1016/j.cell.2011.09.024.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Yuan BZ, Miller MJ, Keck CL, Zimonjic DB, Thorgeirsson SS, Popescu NC. Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer Res. 1998;58(10):2196–9.

    CAS  PubMed  Google Scholar 

  3. Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY, et al. Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. J Biol Chem. 2003;278(12):10824–30. doi:10.1074/jbc.M208310200.

    Article  CAS  PubMed  Google Scholar 

  4. 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(5):1185–207. doi:10.1111/j.1582-4934.2007.00098.x.

    Article  CAS  PubMed  Google Scholar 

  5. Liao YC, Lo SH. Deleted in liver cancer-1 (DLC-1): a tumor suppressor not just for liver. Int J Biochem Cell Biol. 2008;40(5):843–7. doi:10.1016/j.biocel.2007.04.008.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. 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(11):1439–44. doi:10.1101/gad.1672608.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Lahoz A, Hall A. DLC1: a significant GAP in the cancer genome. Genes Dev. 2008;22(13):1724–30. doi:10.1101/gad.1691408.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Lukasik D, Wilczek E, Wasiutynski A, Gornicka B. Deleted in liver cancer protein family in human malignancies (Review). Oncol Lett. 2011;2(5):763–8. doi:10.3892/ol.2011.345.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. El-Sitt S, El-Sibai M. The STAR of the DLC family. J Recept Signal Transduct Res. 2013;33(1):10–3. doi:10.3109/10799893.2012.752002.

    Article  CAS  PubMed  Google Scholar 

  10. Ko FC, Ping Yam JW. Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation. Int J Cancer. Epub 2013 Oct 1. doi:10.1002/ijc.28505.

  11. Homma Y, Emori Y. A dual functional signal mediator showing RhoGAP and phospholipase C-delta stimulating activities. EMBO J. 1995;14(2):286–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Clark EA, King WG, Brugge JS, Symons M, Hynes RO. Integrin-mediated signals regulated by members of the rho family of GTPases. J Cell Biol. 1998;142(2):573–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Sekimata M, Kabuyama Y, Emori Y, Homma Y. Morphological changes and detachment of adherent cells induced by p122, a GTPase-activating protein for Rho. J Biol Chem. 1999;274(25):17757–62.

    Article  CAS  PubMed  Google Scholar 

  14. Jaffe AB, Hall A. Rho GTPases in transformation and metastasis. Adv Cancer Res. 2002;84:57–80.

    Article  CAS  PubMed  Google Scholar 

  15. Lozano J, Xing R, Cai Z, Jensen HL, Trempus C, Mark W, et al. Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. Cancer Res. 2003;63(14):4232–8.

    CAS  PubMed  Google Scholar 

  16. Wong CM, Yam JW, Ching YP, Yau TO, Leung TH, Jin DY, et al. Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma. Cancer Res. 2005;65(19):8861–8. doi:10.1158/0008-5472.can-05-1318.

    Article  CAS  PubMed  Google Scholar 

  17. 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(5):326–37. doi:10.1002/mc.20389.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Kim TY, Lee JW, Kim HP, Jong HS, Jung M, Bang YJ. DLC-1, a GTPase-activating protein for Rho, is associated with cell proliferation, morphology, and migration in human hepatocellular carcinoma. Biochem Biophys Res Commun. 2007;355(1):72–7. doi:10.1016/j.bbrc.2007.01.121.

    Article  CAS  PubMed  Google Scholar 

  19. 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(6):371–81. doi:10.1038/cgt.2008.13.

    Article  CAS  PubMed  Google Scholar 

  20. Wilson KF, Erickson JW, Antonyak MA, Cerione RA. Rho GTPases and their roles in cancer metabolism. Trends Mol Med. 2013;19(2):74–82. doi:10.1016/j.molmed.2012.10.011.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Hall A. The cytoskeleton and cancer. Cancer Metastasis Rev. 2009;28(1–2):5–14. doi:10.1007/s10555-008-9166-3.

    Article  PubMed  Google Scholar 

  22. 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 U S A. 2007;104(21):9012–7. doi:10.1073/pnas.0703033104.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Yang XY, Guan M, Vigil D, Der CJ, Lowy DR, Popescu NC. p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities. Oncogene. 2009;28(11):1401–9. doi:10.1038/onc.2008.498.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Qian X, Durkin ME, Wang D, Tripathi BK, Olson L, Yang XY, et al. Inactivation of the Dlc1 gene cooperates with downregulation of p15INK4b and p16Ink4a, leading to neoplastic transformation and poor prognosis in human cancer. Cancer Res. 2012;72(22):5900–11. doi:10.1158/0008-5472.can-12-2368.

    Article  CAS  PubMed  Google Scholar 

  25. Oliveira AM, Ross JS, Fletcher JA. Tumor suppressor genes in breast cancer: the gatekeepers and the caretakers. Am J Clin Pathol. 2005;124(Suppl):S16–28.

    CAS  PubMed  Google Scholar 

  26. Stafford LJ, Vaidya KS, Welch DR. Metastasis suppressors genes in cancer. Int J Biochem Cell Biol. 2008;40(5):874–91. doi:10.1016/j.biocel.2007.12.016.

    Article  CAS  PubMed  Google Scholar 

  27. Horak CE, Lee JH, Marshall JC, Shreeve SM, Steeg PS. The role of metastasis suppressor genes in metastatic dormancy. APMIS. 2008;116(7–8):586–601. doi:10.1111/j.1600-0463.2008.01213.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Kim TY, Vigil D, Der CJ, Juliano RL. Role of DLC-1, a tumor suppressor protein with RhoGAP activity, in regulation of the cytoskeleton and cell motility. Cancer Metastasis Rev. 2009;28(1–2):77–83. doi:10.1007/s10555-008-9167-2.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Smith SC, Theodorescu D. Learning therapeutic lessons from metastasis suppressor proteins. Nat Rev Cancer. 2009;9(4):253–64. doi:10.1038/nrc2594.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Cook LM, Hurst DR, Welch DR. Metastasis suppressors and the tumor microenvironment. Semin Cancer Biol. 2011;21(2):113–22. doi:10.1016/j.semcancer.2010.12.005.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Thiolloy S, Rinker-Schaeffer CW. Thinking outside the box: using metastasis suppressors as molecular tools. Semin Cancer Biol. 2011;21(2):89–98. doi:10.1016/j.semcancer.2010.12.008.

    Article  CAS  PubMed  Google Scholar 

  32. 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(14):6042–53. doi:10.1158/0008-5472.can-04-3043.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Goodison S, Kawai K, Hihara J, Jiang P, Yang M, Urquidi V, et al. Prolonged dormancy and site-specific growth potential of cancer cells spontaneously disseminated from nonmetastatic breast tumors as revealed by labeling with green fluorescent protein. Clin Cancer Res. 2003;9(10 Pt 1):3808–14.

    CAS  PubMed  Google Scholar 

  34. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3(6):537–49.

    Article  CAS  PubMed  Google Scholar 

  35. Dydensborg AB, Rose AA, Wilson BJ, Grote D, Paquet M, Giguere V, et al. GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis. Oncogene. 2009;28(29):2634–42. doi:10.1038/onc.2009.126.

    Article  CAS  PubMed  Google Scholar 

  36. Guan CN, Zhang PW, Lou HQ, Liao XH, Chen BY. DLC-1 expression levels in breast cancer assessed by qRT-PCR are negatively associated with malignancy. Asian Pac J Cancer Prev. 2012;13(4):1231–3.

    Article  PubMed  Google Scholar 

  37. Yuan BZ, Zhou X, Durkin ME, Zimonjic DB, Gumundsdottir K, Eyfjord JE, et al. DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity. Oncogene. 2003;22(3):445–50. doi:10.1038/sj.onc.1206064.

    Article  CAS  PubMed  Google Scholar 

  38. Voeghtly LM, Mamula K, Campbell JL, Shriver CD, Ellsworth RE. Molecular alterations associated with breast cancer mortality. PLoS One. 2012;7(10):e46814. doi:10.1371/journal.pone.0046814.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Ullmannova V, Popescu NC. Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines. Cancer Detect Prev. 2007;31(2):110–8. doi:10.1016/j.cdp.2007.02.005.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Ullmannova V, Popescu NC. Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors. Int J Oncol. 2006;29(5):1127–32.

    CAS  PubMed  Google Scholar 

  41. Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 1994;54(10):2577–81.

    CAS  PubMed  Google Scholar 

  42. Shih YP, Liao YC, Lin Y, Lo SH. DLC1 negatively regulates angiogenesis in a paracrine fashion. Cancer Res. 2010;70(21):8270–5. doi:10.1158/0008-5472.can-10-1174.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Tripathi V, Popescu NC, Zimonjic DB. DLC1 interaction with alpha-catenin stabilizes adherens junctions and enhances DLC1 antioncogenic activity. Mol Cell Biol. 2012;32(11):2145–59. doi:10.1128/mcb.06580-11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Tripathi V, Popescu NC, Zimonjic DB. DLC1 induces expression of E-cadherin in prostate cancer cells through Rho pathway and suppresses invasion. Oncogene. Epub 2013 Feb 4. doi:10.1038/onc.2013.7.

  45. 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 (review). Int J Oncol. 2012;41(2):393–406. doi:10.3892/ijo.2012.1474.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Qin LX, Tang ZY, Sham JS, Ma ZC, Ye SL, Zhou XD, et al. The association of chromosome 8p deletion and tumor metastasis in human hepatocellular carcinoma. Cancer Res. 1999;59(22):5662–5.

    CAS  PubMed  Google Scholar 

  47. Song LJ, Ye SL, Wang KF, Weng YQ, Liang CM, Sun RX, et al. Relationship between DLC-1 expressions and metastasis in hepatocellular carcinoma [in Chinese]. Zhonghua Gan Zang Bing Za Zhi. 2005;13(6):428–31.

    CAS  PubMed  Google Scholar 

  48. Mas VR, Fisher RA, Archer KJ, Yanek KC, Williams B, Dumur CI, et al. Genes associated with progression and recurrence of hepatocellular carcinoma in hepatitis C patients waiting and undergoing liver transplantation: preliminary results. Transplantation. 2007;83(7):973–81. doi:10.1097/01.tp.0000258643.05294.0b.

    Article  PubMed  Google Scholar 

  49. 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(6):1308–13. doi:10.1038/sj.onc.1207246.

    Article  CAS  PubMed  Google Scholar 

  50. Zhou X, Zimonjic DB, Park SW, Yang XY, Durkin ME, Popescu NC. DLC1 suppresses distant dissemination of human hepatocellular carcinoma cells in nude mice through reduction of RhoA GTPase activity, actin cytoskeletal disruption and down-regulation of genes involved in metastasis. Int J Oncol. 2008;32(6):1285–91.

    CAS  PubMed  Google Scholar 

  51. Ko FC, Chan LK, Tung EK, Lowe SW, Ng IO, Yam JW. Akt phosphorylation of deleted in liver cancer 1 abrogates its suppression of liver cancer tumorigenesis and metastasis. Gastroenterology. 2010;139(4):1397–407. doi:10.1053/j.gastro.2010.06.051.

    Article  CAS  PubMed  Google Scholar 

  52. Ko FC, Chan LK, Sze KM, Yeung YS, Tse EY, Lu P, et al. PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis. Nat Commun. 2013;4:1618. doi:10.1038/ncomms2604.

    Article  PubMed  Google Scholar 

  53. Ng IO, Liang ZD, Cao L, Lee TK. DLC-1 is deleted in primary hepatocellular carcinoma and exerts inhibitory effects on the proliferation of hepatoma cell lines with deleted DLC-1. Cancer Res. 2000;60(23):6581–4.

    CAS  PubMed  Google Scholar 

  54. Andersen JB, Factor VM, Marquardt JU, Raggi C, Lee YH, Seo D, et al. An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer. Sci Transl Med. 2010;2(54):54ra77. doi:10.1126/scitranslmed.3001338.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Hampl V, Martin C, Aigner A, Hoebel S, Singer S, Frank N, et al. Depletion of the transcriptional coactivators megakaryoblastic leukaemia 1 and 2 abolishes hepatocellular carcinoma xenograft growth by inducing oncogene-induced senescence. EMBO Mol Med. 2013;5(9):1367–82. doi:10.1002/emmm.201202406.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Yuan BZ, Jefferson AM, Baldwin KT, Thorgeirsson SS, Popescu NC, Reynolds SH. DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas. Oncogene. 2004;23(7):1405–11. doi:10.1038/sj.onc.1207291.

    Article  CAS  PubMed  Google Scholar 

  57. Yang X, Popescu NC, Zimonjic DB. DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism. Cancer Res. 2011;71(8):2916–25. doi:10.1158/0008-5472.can-10-2158.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Du X, Qian X, Papageorge A, Schetter AJ, Vass WC, Liu X, et al. Functional interaction of tumor suppressor DLC1 and caveolin-1 in cancer cells. Cancer Res. 2012;72(17):4405–16. doi:10.1158/0008-5472.can-12-0777.

    Article  CAS  PubMed  Google Scholar 

  59. Pacurari M, Addison JB, Bondalapati N, Wan YW, Luo D, Qian Y, et al. The microRNA-200 family targets multiple non-small cell lung cancer prognostic markers in H1299 cells and BEAS-2B cells. Int J Oncol. 2013;43(2):548–60. doi:10.3892/ijo.2013.1963.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Bourboulia D, Han H, Jensen-Taubman S, Gavil N, Isaac B, Wei B, et al. TIMP-2 modulates cancer cell transcriptional profile and enhances E-cadherin/beta-catenin complex expression in A549 lung cancer cells. Oncotarget. 2013;4(1):166–76.

    PubMed  Google Scholar 

  61. Castro M, Grau L, Puerta P, Gimenez L, Venditti J, Quadrelli S, et al. Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in lung cancer. J Transl Med. 2010;8:86. doi:10.1186/1479-5876-8-86.

    Article  PubMed Central  PubMed  Google Scholar 

  62. Wan YW, Sabbagh E, Raese R, Qian Y, Luo D, Denvir J, et al. Hybrid models identified a 12-gene signature for lung cancer prognosis and chemoresponse prediction. PLoS One. 2010;5(8):e12222. doi:10.1371/journal.pone.0012222.

    Article  PubMed Central  PubMed  Google Scholar 

  63. Akagi I, Okayama H, Schetter AJ, Robles AI, Kohno T, Bowman ED, et al. Combination of protein coding and noncoding gene expression as a robust prognostic classifier in stage I lung adenocarcinoma. Cancer Res. 2013;73(13):3821–32. doi:10.1158/0008-5472.can-13-0031.

    Article  CAS  PubMed  Google Scholar 

  64. Ullmannova-Benson V, Guan M, Zhou X, Tripathi V, Yang XY, Zimonjic DB, et al. DLC1 tumor suppressor gene inhibits migration and invasion of multiple myeloma cells through RhoA GTPase pathway. Leukemia. 2009;23(2):383–90. doi:10.1038/leu.2008.285.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Jung S, Kim S, Gale M, Cherni I, Fonseca R, Carpten J, et al. DNA methylation in multiple myeloma is weakly associated with gene transcription. PLoS One. 2012;7(12):e52626. doi:10.1371/journal.pone.0052626.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Fan DM, Shi HR. Pilot study: alteration of deleted in liver cancer1 and phosphorylated focal adhesion kinase Y397 cytoplasmic expression and the prognostic value in advanced epithelial ovarian carcinoma. Int J Mol Sci. 2011;12(12):8489–501. doi:10.3390/ijms12128489.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Ren F, Shi H, Zhang G, Zhang R. Expression of deleted in liver cancer 1 and plasminogen activator inhibitor 1 protein in ovarian carcinoma and their clinical significance. J Exp Clin Cancer Res. 2013;32(1):60. doi:10.1186/1756-9966-32-60.

    Article  PubMed Central  PubMed  Google Scholar 

  68. Zhang T, Zheng J, Liu C, Lu Y. Expression of DLC-1 in clear cell renal cell carcinoma: prognostic significance for progression and metastasis. Urol Int. 2009;82(4):380–7. doi:10.1159/000218524.

    Article  CAS  PubMed  Google Scholar 

  69. Chen WT, Yang CH, Wu CC, Huang YC, Chai CY. Aberrant deleted in liver cancer-1 expression is associated with tumor metastasis and poor prognosis in urothelial carcinoma. APMIS. Epub 2013 Mar 20. doi:10.1111/apm.12060.

  70. Yuan BZ, Jefferson AM, Millecchia L, Popescu NC, Reynolds SH. Morphological changes and nuclear translocation of DLC1 tumor suppressor protein precede apoptosis in human non-small cell lung carcinoma cells. Exp Cell Res. 2007;313(18):3868–80. doi:10.1016/j.yexcr.2007.08.009.

    Article  CAS  PubMed  Google Scholar 

  71. 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(17):8367–72. doi:10.1158/0008-5472.can-05-2850.

    Article  CAS  PubMed  Google Scholar 

  72. Cao X, Voss C, Zhao B, Kaneko T, Li SS. Differential regulation of the activity of deleted in liver cancer 1 (DLC1) by tensins controls cell migration and transformation. Proc Natl Acad Sci U S A. 2012;109(5):1455–60. doi:10.1073/pnas.1114368109.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Heering J, Erlmann P, Olayioye MA. Simultaneous loss of the DLC1 and PTEN tumor suppressors enhances breast cancer cell migration. Exp Cell Res. 2009;315(15):2505–14. doi:10.1016/j.yexcr.2009.05.022.

    Article  CAS  PubMed  Google Scholar 

  74. Weber GF. Why does cancer therapy lack effective anti-metastasis drugs? Cancer Lett. 2013;328(2):207–11. doi:10.1016/j.canlet.2012.09.025.

    Article  CAS  PubMed  Google Scholar 

  75. Lu J, Chan L, Fiji HD, Dahl R, Kwon O, Tamanoi F. In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I. Mol Cancer Ther. 2009;8(5):1218–26. doi:10.1158/1535-7163.mct-08-1122.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Zimonjic DB, Chan LN, Tripathi V, Lu J, Kwon O, Popescu NC, et al. In vitro and in vivo effects of geranylgeranyltransferase I inhibitor P61A6 on non-small cell lung cancer cells. BMC Cancer. 2013;13:198. doi:10.1186/1471-2407-13-198.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Vigil D, Kim TY, Plachco A, Garton AJ, Castaldo L, Pachter JA, et al. ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion. Cancer Res. 2012;72(20):5338–47. doi:10.1158/0008-5472.can-11-2373.

    Article  CAS  PubMed  Google Scholar 

  78. Michod D, Yang JY, Chen J, Bonny C, Widmann C. A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells. Oncogene. 2004;23(55):8971–8. doi:10.1038/sj.onc.1207999.

    Article  CAS  PubMed  Google Scholar 

  79. Barras D, Lorusso G, Ruegg C, Widmann C. Inhibition of cell migration and invasion mediated by the TAT-RasGAP peptide requires the DLC1 tumor suppressor. Oncogene. Epub 2013 Nov 11. doi:10.1038/onc.2013.465.

  80. Yuan BZ, Durkin ME, Popescu NC. Promoter hypermethylation of DLC-1, a candidate tumor suppressor gene, in several common human cancers. Cancer Genet Cytogenet. 2003;140(2):113–7.

    Article  CAS  PubMed  Google Scholar 

  81. Liu JB, Zhang SQ, Shi MX, Shao BF, Zhang YX. Relationship between methylation status of DLC-1 gene and metastasis of hepatocellular carcinoma. World Chin J Digestol. 2008;11:1237–40.

    Google Scholar 

  82. Xue YZ, Wu TL, Wu YM, Sheng YY, Wei ZQ, Lu YF, et al. DLC-1 is a candidate biomarker methylated and down-regulated in pancreatic ductal adenocarcinoma. Tumour Biol. 2013;34(5):2857–61. doi:10.1007/s13277-013-0846-4.

    Article  CAS  PubMed  Google Scholar 

  83. Feng X, Ren C, Zhou W, Liu W, Zeng L, Li G, et al. Promoter Hypermethylation Along With LOH, But Not Mutation, Contributes to Inactivation of DLC-1 in Nasopharyngeal Carcinoma. Mol Carcinog. Epub 2013 Jun 12. doi:10.1002/mc.22044.

  84. Zhou X, Yang XY, Popescu NC. Preclinical evaluation of combined antineoplastic effect of DLC1 tumor suppressor protein and suberoylanilide hydroxamic acid on prostate cancer cells. Biochem Biophys Res Commun. 2012;420(2):325–30. doi:10.1016/j.bbrc.2012.02.158.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Au SL, Wong CC, Lee JM, Wong CM, Ng IO. EZH2-mediated H3K27me3 is involved in epigenetic repression of deleted in liver cancer 1 in human cancers. PLoS One. 2013;8(6):e68226. doi:10.1371/journal.pone.0068226.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res. 2008;647(1–2):21–9. doi:10.1016/j.mrfmmm.2008.07.010.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Supported in part by National Cancer Institute Grants RO1 CA116161 (SG) and R44 CA173921 (SG). Dr. Popescu is a co-inventor on a patent for the potential use of DLC1 in oncology. Dr. Goodison has no conflicts to disclose.

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  1. Laboratory of Experimental Carcinogenesis, National Cancer Institute, Building 37, Room 4140, 37 Convent Dr., MSC 4262, Bethesda, MD, 20892-4262, USA

    Nicholas C. Popescu

  2. Department of Health Sciences Research, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Steve Goodison

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Popescu, N.C., Goodison, S. Deleted in Liver Cancer-1 (DLC1): An Emerging Metastasis Suppressor Gene. Mol Diagn Ther 18, 293–302 (2014). https://doi.org/10.1007/s40291-014-0086-3

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