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Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1

Abstract

Enhanced expression of the CCN family of secretory integrin-binding proteins correlates with many essential components of the cancerous state, including tumor cell adhesion, proliferation, invasion and migration. Consequently, CCN1 expression is elevated in various cancers, including breast cancer, and its expression directly correlates with poor patient prognosis. Using subtraction–hybridization, combined with induction of cancer cell terminal differentiation, we cloned SARI (suppressor of activator protein (AP)-1, regulated by interferon (IFN)), an IFN-β-inducible, potent tumor suppressor gene that exerts cancer-selective growth inhibitory effects. Forced expression of SARI using an adenovirus (Ad.SARI) inhibits AP-1 function and downregulates CCN1 expression in multiple cancer lineages, resulting in a profound inhibition in anchorage-independent cell growth and tumor cell invasion. Overexpression of SARI reduces CCN1-promoter activity through inhibition of AP-1 binding. Accordingly, SARI selectively blocks expression of the transformed state in rat embryo fibroblast cells that stably overexpress c-Jun. These results illustrate that SARI inhibits AP-1 transactivating factor binding to the cis-element of the CCN1 promoter, possibly through its interaction with c-Jun. Overall, SARI can directly inhibit CCN1-induced transformation by inhibiting the transcription of CCN1, as well as indirectly by inhibiting the expression of c-Jun (and hence blocking AP-1 activity). In these contexts, transformed cells ‘addicted’ to AP-1 activity are rendered susceptible to SARI-mediated inhibition of expression of the transformed phenotype.

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References

  • Angel P, Karin M . (1991). The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1072: 129–157.

    CAS  PubMed  Google Scholar 

  • Bork P . (1993). The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett 327: 125–130.

    Article  CAS  PubMed  Google Scholar 

  • Brigstock DR . (1999). The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 20: 189–206.

    CAS  PubMed  Google Scholar 

  • Chen CC, Mo FE, Lau LF . (2001). The angiogenic factor Cyr61 activates a genetic program for wound healing in human skin fibroblasts. J Biol Chem 276: 47329–47337.

    Article  CAS  PubMed  Google Scholar 

  • Chinenov Y, Kerppola TK . (2001). Close encounters of many kinds: Fos-Jun interactions that mediate transcription regulatory specificity. Oncogene 20: 2438–2452.

    Article  CAS  PubMed  Google Scholar 

  • Dash R, Dmitriev I, Su ZZ, Bhutia SK, Azab B, Vozhilla N et al. (2010). Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) improves therapeutic efficacy in low CAR prostate cancer cells. Cancer Gene Ther.

  • Echlin DR, Tae HJ, Mitin N, Taparowsky EJ . (2000). B-ATF functions as a negative regulator of AP-1 mediated transcription and blocks cellular transformation by Ras and Fos. Oncogene 19: 1752–1763.

    Article  CAS  PubMed  Google Scholar 

  • Eferl R, Wagner EF . (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3: 859–868.

    Article  CAS  PubMed  Google Scholar 

  • Felding-Habermann B, O'Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH et al. (2001). Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA 98: 1853–1858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gery S, Xie D, Yin D, Gabra H, Miller C, Wang H et al. (2005). Ovarian carcinomas: CCN genes are aberrantly expressed and CCN1 promotes proliferation of these cells. Clin Cancer Res 11: 7243–7254.

    Article  CAS  PubMed  Google Scholar 

  • Grotendorst GR, Lau LF, Perbal B . (2000). CCN proteins are distinct from and should not be considered members of the insulin-like growth factor-binding protein superfamily. Endocrinology 141: 2254–2256.

    Article  CAS  PubMed  Google Scholar 

  • Han JS, Macarak E, Rosenbloom J, Chung KC, Chaqour B . (2003). Regulation of Cyr61/CCN1 gene expression through RhoA GTPase and p38MAPK signaling pathways. Eur J Biochem 270: 3408–3421.

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ . (2009). Cancer statistics, 2009. CA Cancer J Clin 59: 225–249.

    Article  PubMed  Google Scholar 

  • Jiang H, Fisher PB . (1993). Use of a sensitive and efficient subtraction hybridization protocol for the identification of genes differentially regulated during the induction of differentiation in human melanoma cells. Mol Cell Differentiation 1: 285–299.

    CAS  Google Scholar 

  • Jiang WG, Watkins G, Fodstad O, Douglas-Jones A, Mokbel K, Mansel RE . (2004). Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer. Endocr Relat Cancer 11: 781–791.

    Article  CAS  PubMed  Google Scholar 

  • Lebedeva IV, Su ZZ, Chang Y, Kitada S, Reed JC, Fisher PB . (2002). The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells. Oncogene 21: 708–718.

    Article  CAS  PubMed  Google Scholar 

  • Lebedeva IV, Sarkar D, Su ZZ, Kitada S, Dent P, Stein CA et al. (2003). Bcl-2 and Bcl-x(L) differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24. Oncogene 22: 8758–8773.

    Article  CAS  PubMed  Google Scholar 

  • Lee SG, Su ZZ, Emdad L, Sarkar D, Franke TF, Fisher PB . (2008). Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. Oncogene 27: 1114–1121.

    Article  CAS  PubMed  Google Scholar 

  • Leu SJ, Chen N, Chen CC, Todorovic V, Bai T, Juric V et al. (2004). Targeted mutagenesis of the angiogenic protein CCN1 (CYR61). Selective inactivation of integrin alpha6beta1-heparan sulfate proteoglycan coreceptor-mediated cellular functions. J Biol Chem 279: 44177–44187.

    Article  CAS  PubMed  Google Scholar 

  • Ludes-Meyers JH, Liu Y, Munoz-Medellin D, Hilsenbeck SG, Brown PH . (2001). AP-1 blockade inhibits the growth of normal and malignant breast cells. Oncogene 20: 2771–2780.

    Article  CAS  PubMed  Google Scholar 

  • Maki Y, Bos TJ, Davis C, Starbuck M, Vogt PK . (1987). Avian sarcoma virus 17 carries the jun oncogene. Proc Natl Acad Sci USA 84: 2848–2852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matthews CP, Colburn NH, Young MR . (2007). AP-1 a target for cancer prevention. Curr Cancer Drug Targets 7: 317–324.

    Article  CAS  PubMed  Google Scholar 

  • Menendez JA, Vellon L, Mehmi I, Teng PK, Griggs DW, Lupu R . (2005). A novel CYR61-triggered ‘′CYR61-alphavbeta3 integrin loop′’ regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway. Oncogene 24: 761–779.

    Article  CAS  PubMed  Google Scholar 

  • Nguyen N, Kuliopulos A, Graham RA, Covic L . (2006). Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells. Cancer Res 66: 2658–2665.

    Article  CAS  PubMed  Google Scholar 

  • O'Kelly J, Chung A, Lemp N, Chumakova K, Yin D, Wang HJ et al. (2008). Functional domains of CCN1 (Cyr61) regulate breast cancer progression. Int J Oncol 33: 59–67.

    CAS  PubMed  Google Scholar 

  • O'Kelly KH . (2005). The role of CCN1 in tumorigenesis and cancer progression. In: PB (ed). CCN Proteins. Imperial College Press: London, UK.

    Google Scholar 

  • Roskelley CD, Bissell MJ . (2002). The dominance of the microenvironment in breast and ovarian cancer. Semin Cancer Biol 12: 97–104.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ryseck RP, Bravo R . (1991). c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences: effect of FOS proteins. Oncogene 6: 533–542.

    CAS  PubMed  Google Scholar 

  • Sarkar D, Su ZZ, Vozhilla N, Park ES, Gupta P, Fisher PB . (2005). Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Proc Natl Acad Sci USA 102: 14034–14039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schraml BU, Hildner K, Ise W, Lee W-L, Smith WA, Solomon B et al. (2009). The AP-1 transcription factor Batf controls TH17 differentiation. Nature 460: 405–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimizu T, Okayama A, Inoue T, Takeda K . (2005). Analysis of gene expression during staurosporine-induced neuronal differentiation of human prostate cancer cells. Oncol Rep 14: 441–448.

    CAS  PubMed  Google Scholar 

  • Su Z, Shi Y, Friedman R, Qiao L, McKinstry R, Hinman D et al. (2001). PEA3 sites within the progression elevated gene-3 (PEG-3) promoter and mitogen-activated protein kinase contribute to differential PEG-3 expression in Ha-ras and v-raf oncogene transformed rat embryo cells. Nucleic Acids Res 29: 1661–1671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su ZZ, Madireddi MT, Lin JJ, Young CS, Kitada S, Reed JC et al. (1998). The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci USA 95: 14400–14405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su ZZ, Lebedeva IV, Sarkar D, Gopalkrishnan RV, Sauane M, Sigmon C et al. (2003). Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner. Oncogene 22: 1164–1180.

    Article  CAS  PubMed  Google Scholar 

  • Su ZZ, Lee SG, Emdad L, Lebdeva IV, Gupta P, Valerie K et al. (2008). Cloning and characterization of SARI (suppressor of AP-1, regulated by IFN). Proc Natl Acad Sci USA 105: 20906–20911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taddei I, Faraldo MM, Teuliere J, Deugnier MA, Thiery JP, Glukhova MA . (2003). Integrins in mammary gland development and differentiation of mammary epithelium. J Mammary Gland Biol Neoplasia 8: 383–394.

    Article  PubMed  Google Scholar 

  • Tsai MS, Bogart DF, Castaneda JM, Li P, Lupu R . (2002a). Cyr61 promotes breast tumorigenesis and cancer progression. Oncogene 21: 8178–8185.

    Article  CAS  PubMed  Google Scholar 

  • Tsai MS, Bogart DF, Li P, Mehmi I, Lupu R . (2002b). Expression and regulation of Cyr61 in human breast cancer cell lines. Oncogene 21: 964–973.

    Article  CAS  PubMed  Google Scholar 

  • Vandel L, Montreau N, Vial E, Pfarr CM, Binetruy B, Castellazzi M . (1996). Stepwise transformation of rat embryo fibroblasts: c-Jun, JunB, or JunD can cooperate with Ras for focus formation, but a c-Jun-containing heterodimer is required for immortalization. Mol Cell Biol 16: 1881–1888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vellon L, Menendez JA, Lupu R . (2005). AlphaVbeta3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer. Oncogene 24: 3759–3773.

    Article  CAS  PubMed  Google Scholar 

  • Williams KL, Nanda I, Lyons GE, Kuo CT, Schmid M, Leiden JM et al. (2001). Characterization of murine BATF: a negative regulator of activator protein-1 activity in the thymus. Eur J Immunol 31: 1620–1627.

    Article  CAS  PubMed  Google Scholar 

  • Wingender E, Chen X, Hehl R, Karas H, Liebich I, Matys V et al. (2000). TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Res 28: 316–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie D, Miller CW, O'Kelly J, Nakachi K, Sakashita A, Said JW et al. (2001). Breast cancer. Cyr61 is overexpressed, estrogen-inducible, and associated with more advanced disease. J Biol Chem 276: 14187–14194.

    Article  CAS  PubMed  Google Scholar 

  • Zullo AJ, Benlagha K, Bendelac A, Taparowsky EJ . (2007). Sensitivity of NK1.1 negative NKT cells to transgenic BATF defines a role for activator protein-1 in the expansion and maturation of immature NKT cells in the thymus. J Immunol 178: 58–66.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported in part by National Institutes of Health Grants R01 CA097318 and P01 CA104177; and by the National Foundation for Cancer Research. DS is a Harrison Endowed Scholar in Cancer Research. PBF holds the Thelma Newmeyer Corman Chair in Cancer Research.

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Correspondence to P B Fisher.

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Dash, R., Su, ZZ., Lee, SG. et al. Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1. Oncogene 29, 4412–4423 (2010). https://doi.org/10.1038/onc.2010.194

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