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Deleted in liver cancer 3 (DLC-3), a novel Rho GTPase-activating protein, is downregulated in cancer and inhibits tumor cell growth

Oncogene volume 26, pages 4580–4589 (2007)Cite this article

Abstract

Two related Rho GTPase-activating proteins, DLC-1 (deleted in liver cancer 1) and DLC-2, are emerging as bona fide tumor suppressor genes that inhibit cancer cell growth. In this report, we characterized a gene on chromosome Xq13 that encodes DLC-3 (also known as KIAA0189 and STARD8), a third member of the DLC family. The DLC-3 gene has transcripts with alternative 5′ ends, one of which, DLC-3α, encodes an 1103-amino acid polypeptide highly similar to DLC-1 and DLC-2. A second isoform (DLC-3β) would yield a protein lacking the N-terminal sterile alpha motif domain. The DLC-3 gene is widely expressed in normal tissues, but DLC-3 mRNA levels were low or absent in a significant number of breast, ovarian, liver and prostate cancer cell lines. Using a cancer profiling array to compare matched tumor and normal human tissues, downregulation of DLC-3 mRNA was observed in kidney, lung, ovarian, uterine and breast cancer samples. By quantitative reverse transcriptase–polymerase chain reaction, DLC-3 expression was reduced in primary prostate carcinomas relative to normal prostate tissue. Transfection of human breast and prostate cancer cells with a DLC-3α expression vector inhibited cell proliferation, colony formation and growth in soft agar. These results indicate that deregulation of DLC-3 may contribute to breast and prostate tumorigenesis.

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References

  • Alpy F, Tomasetto C . (2005). Give lipids a START: the StAR-related lipid transfer (START) domain in mammals. J Cell Sci 118: 2791–2801.

    Article  CAS  PubMed  Google Scholar 

  • Avila DM, Zoppi S, McPhaul MJ . (2001). The androgen receptor (AR) in syndromes of androgen insensitivity and in prostate cancer. J Steroid Biochem Mol Biol 76: 135–142.

    Article  CAS  PubMed  Google Scholar 

  • Bernards A . (2003). GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim Biophys Acta 1603: 47–82.

    CAS  PubMed  Google Scholar 

  • Bernards A, Settleman J . (2004). GAP control: regulating the regulators of small GTPases. Trends Cell Biol 14: 377–385.

    Article  CAS  PubMed  Google Scholar 

  • Billuart P, Bienvenu T, Ronce N, des Portes V, Vinet MC, Zemni R et al. (1998). Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation. Nature 392: 923–926.

    Article  CAS  PubMed  Google Scholar 

  • Brown MC, Curtis MS, Turner CE . (1998). Paxillin LD motifs may define a new family of protein recognition domains. Nat Struct Biol 5: 677–678.

    Article  CAS  PubMed  Google Scholar 

  • Carrel L, Willard HF . (2005). X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434: 400–404.

    Article  CAS  PubMed  Google Scholar 

  • Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY et al. (2003). Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. J Biol Chem 278: 10824–10830.

    Article  CAS  PubMed  Google Scholar 

  • Denholm B, Brown S, Ray RP, Ruiz-Gomez M, Skaer H, Hombria JC . (2005). crossveinless-c is a RhoGAP required for actin reorganisation during morphogenesis. Development 132: 2389–2400.

    Article  CAS  PubMed  Google Scholar 

  • Durkin ME, Avner MR, Huh CG, Yuan BZ, Thorgeirsson SS, Popescu NC . (2005). DLC-1, a Rho GTPase-activating protein with tumor suppressor function, is essential for embryonic development. FEBS Lett 579: 1191–1196.

    Article  CAS  PubMed  Google Scholar 

  • Durkin ME, Yuan BZ, Thorgeirsson SS, Popescu NC . (2002). Gene structure, tissue expression, and linkage mapping of the mouse DLC-1 gene (Arhgap7). Gene 288: 119–127.

    Article  CAS  PubMed  Google Scholar 

  • Edelson MI, Lau CC, Colitti CV, Welch WR, Bell DA, Berkowitz RS et al. (1998). A one centimorgan deletion unit on chromosome Xq12 is commonly lost in borderline and invasive epithelial ovarian tumors. Oncogene 16: 197–202.

    Article  CAS  PubMed  Google Scholar 

  • Gomez del Pulgar T, Benitah SA, Valeron PF, Espina C, Lacal JC . (2005). Rho GTPase expression in tumourigenesis: evidence for a significant link. Bioessays 27: 602–613.

    Article  PubMed  Google Scholar 

  • Goodison S, Yuan J, Sloan D, Kim R, Li C, Popescu NC et al. (2005). The RhoGAP protein DLC-1 functions as a metastasis suppressor in breast cancer cells. Cancer Res 65: 6042–6053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guan M, Zhou X, Soulitzis N, Spandidos DA, Popescu NC . (2006). Aberrant methylation and deacetylation of deleted in liver cancer-1 gene in prostate cancer: potential clinical applications. Clin Cancer Res 12: 1412–1419.

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  PubMed  Google Scholar 

  • Hers I, Wherlock M, Homma Y, Yagisawa H, Tavare JM . (2006). Identification of p122RhoGAP (deleted in liver cancer-1) Serine 322 as a substrate for protein kinase B and ribosomal S6 kinase in insulin-stimulated cells. J Biol Chem 281: 4762–4770.

    Article  CAS  PubMed  Google Scholar 

  • Homma Y, Emori Y . (1995). A dual functional signal mediator showing RhoGAP and phospholipase C-delta stimulating activities. EMBO J 14: 286–291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaffe AB, Hall A . (2005). Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21: 247–269.

    Article  CAS  PubMed  Google Scholar 

  • Leung TH, Ching YP, Yam JW, Wong CM, Yau TO, Jin DY et al. (2005). Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity. Proc Natl Acad Sci USA 102: 15207–15212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li SS . (2005). Specificity and versatility of SH3 and other proline-recognition domains: structural basis and implications for cellular signal transduction. Biochem J 390: 641–653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McLysaght A, Hokamp K, Wolfe KH . (2002). Extensive genomic duplication during early chordate evolution. Nat Genet 31: 200–204.

    Article  CAS  PubMed  Google Scholar 

  • Moon SY, Zheng Y . (2003). Rho GTPase-activating proteins in cell regulation. Trends Cell Biol 13: 13–22.

    Article  CAS  PubMed  Google Scholar 

  • Murakami T, Sakane F, Imai S, Houkin K, Kanoh H . (2003). Identification and characterization of two splice variants of human diacylglycerol kinase η. J Biol Chem 278: 34364–34372.

    Article  CAS  PubMed  Google Scholar 

  • Nagaraja GM, Kandpal RP . (2004). Chromosome 13q12 encoded Rho GTPase activating protein suppresses growth of breast carcinoma cells, and yeast two-hybrid screen shows its interaction with several proteins. Biochem Biophys Res Commun 313: 654–665.

    Article  CAS  PubMed  Google Scholar 

  • Nagase T, Seki N, Ishikawa K, Tanaka A, Nomura N . (1996). Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res 3: 17–24.

    Article  CAS  PubMed  Google Scholar 

  • Ng IO, Liang ZD, Cao L, Lee TK . (2000). 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 60: 6581–6584.

    CAS  PubMed  Google Scholar 

  • Ponting CP, Aravind L . (1999). START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins. Trends Biochem Sci 24: 130–132.

    Article  CAS  PubMed  Google Scholar 

  • Qiao F, Bowie JU . (2005). The many faces of SAM. Sci STKE 2005: re7.

    PubMed  Google Scholar 

  • Ridley AJ . (2001). Rho family proteins: coordinating cell responses. Trends Cell Biol 11: 471–477.

    Article  CAS  PubMed  Google Scholar 

  • Sekimata M, Kabuyama Y, Emori Y, Homma Y . (1999). Morphological changes and detachment of adherent cells induced by p122, a GTPase-activating protein for Rho. J Biol Chem 274: 17757–17762.

    Article  CAS  PubMed  Google Scholar 

  • Seng TJ, Low JS, Li H, Cui Y, Goh HK, Wong ML et al. (2006). The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation. Oncogene [Epub ahead of print].

  • Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD et al. (2006). The consensus coding sequences of human breast and colorectal cancers. Science 314: 268–274.

    Article  PubMed  Google Scholar 

  • Song YF, Xu R, Zhang XH, Chen BB, Chen Q, Chen YM et al. (2006). High-frequency promoter hypermethylation of the deleted in liver cancer-1 gene in multiple myeloma. J Clin Pathol 59: 947–951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spatz A, Borg C, Feunteun J . (2004). X-chromosome genetics and human cancer. Nat Rev Cancer 4: 617–629.

    Article  CAS  PubMed  Google Scholar 

  • Syed V, Mukherjee K, Lyons-Weiler J, Lau KM, Mashima T, Tsuruo T et al. (2005). Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling. Oncogene 24: 1774–1787.

    Article  CAS  PubMed  Google Scholar 

  • Thakur A, Xu H, Wang Y, Bollig A, Biliran H, Liao JD . (2005). The role of X-linked genes in breast cancer. Breast Cancer Res Treat 93: 135–143.

    Article  CAS  PubMed  Google Scholar 

  • Twigg SR, Mastumoto K, Kidd AM, Goriely A, Taylor IB, Fisher RB et al. (2006). The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males. Am J Hum Genet 78: 999–1010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ullmannova V, Popescu NC . (2006). Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors. Int J Oncol 29: 1127–1132.

    CAS  PubMed  Google Scholar 

  • Van Aelst L, D’Souza-Schorey C . (1997). Rho GTPases and signaling networks. Genes Dev 11: 2295–2322.

    Article  CAS  PubMed  Google Scholar 

  • Wieland I, Jakubiczka S, Muschke P, Cohen M, Thiele H, Gerlach KL et al. (2004). Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet 74: 1209–1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong CM, Lee JM, Ching YP, Jin DY, Ng IO . (2003). Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer Res 63: 7646–7651.

    CAS  PubMed  Google Scholar 

  • Wong CM, Yam JW, Ching YP, Yau TO, Leung TH, Jin DY et al. (2005). Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma. Cancer Res 65: 8861–8868.

    Article  CAS  PubMed  Google Scholar 

  • Yuan BZ, Jefferson AM, Baldwin KT, Thorgeirsson SS, Popescu NC, Reynolds SH . (2004). DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas. Oncogene 23: 1405–1411.

    Article  CAS  PubMed  Google Scholar 

  • Yuan BZ, Miller MJ, Keck CL, Zimonjic DB, Thorgeirsson SS, Popescu NC . (1998). Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer Res 58: 2196–2199.

    CAS  PubMed  Google Scholar 

  • Yuan BZ, Zhou X, Durkin ME, Zimonjic DB, Gumundsdottir K, Eyfjord JE et al. (2003). DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity. Oncogene 22: 445–450.

    Article  CAS  PubMed  Google Scholar 

  • Zhou X, Thorgeirsson SS, Popescu NC . (2004). Restoration of DLC-1 gene expression induces apoptosis and inhibits both cell growth and tumorigenicity in human hepatocellular carcinoma cells. Oncogene 23: 1308–1313.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Intramural Research Program of the National Cancer Institute, NIH.

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  1. M E Durkin and V Ullmannova: These two authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    M E Durkin, V Ullmannova, M Guan & N C Popescu

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  1. M E Durkin
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Correspondence to N C Popescu.

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Durkin, M., Ullmannova, V., Guan, M. et al. Deleted in liver cancer 3 (DLC-3), a novel Rho GTPase-activating protein, is downregulated in cancer and inhibits tumor cell growth. Oncogene 26, 4580–4589 (2007). https://doi.org/10.1038/sj.onc.1210244

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