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The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer

Abstract

The neuronal repellent SLIT2 is repressed in a number of cancer types primarily through promoter hypermethylation. SLIT2, however, has not been studied in prostate cancer. Through genome-wide location analysis we identified SLIT2 as a target of polycomb group (PcG) protein EZH2. The EZH2-containing polycomb repressive complexes bound to the SLIT2 promoter inhibiting its expression. SLIT2 was downregulated in a majority of metastatic prostate tumors, showing a negative correlation with EZH2. This repressed expression could be restored by methylation inhibitors or EZH2-suppressing compounds. In addition, a low level of SLIT2 expression was associated with aggressive prostate, breast and lung cancers. Functional assays showed that SLIT2 inhibited prostate cancer cell proliferation and invasion. Thus, this study showed for the first time the epigenetic silencing of SLIT2 in prostate tumors, and supported SLIT2 as a potential biomarker for aggressive solid tumors. Importantly, PcG-mediated repression may serve as a precursor for the silencing of SLIT2 by DNA methylation in cancer.

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References

  • Astuti D, Da Silva NF, Dallol A, Gentle D, Martinsson T, Kogner P et al. (2004). SLIT2 promoter methylation analysis in neuroblastoma, Wilms’ tumour and renal cell carcinoma. Br J Cancer 90: 515–521.

    Article  CAS  Google Scholar 

  • Beke L, Nuytten M, Van Eynde A, Beullens M, Bollen M . (2007). The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2. Oncogene 26: 4590–4595.

    Article  CAS  Google Scholar 

  • Brose K, Bland KS, Wang KH, Arnott D, Henzel W, Goodman CS et al. (1999). Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96: 795–806.

    Article  CAS  Google Scholar 

  • Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA et al. (2008). Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27: 7274–7284.

    Article  CAS  Google Scholar 

  • Chen H, Tu SW, Hsieh JT . (2005). Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer. J Biol Chem 280: 22437–22444.

    Article  CAS  Google Scholar 

  • Dallol A, Da Silva NF, Viacava P, Minna JD, Bieche I, Maher ER et al. (2002). SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. Cancer Res 62: 5874–5880.

    CAS  Google Scholar 

  • Dallol A, Krex D, Hesson L, Eng C, Maher ER, Latif F . (2003a). Frequent epigenetic inactivation of the SLIT2 gene in gliomas. Oncogene 22: 4611–4616.

    Article  CAS  Google Scholar 

  • Dallol A, Morton D, Maher ER, Latif F . (2003b). SLIT2 axon guidance molecule is frequently inactivated in colorectal cancer and suppresses growth of colorectal carcinoma cells. Cancer Res 63: 1054–1058.

    CAS  PubMed  Google Scholar 

  • Dammann R, Schagdarsurengin U, Seidel C, Strunnikova M, Rastetter M, Baier K et al. (2005a). The tumor suppressor RASSF1A in human carcinogenesis: an update. Histol Histopathol 20: 645–663.

    CAS  Google Scholar 

  • Dammann R, Strunnikova M, Schagdarsurengin U, Rastetter M, Papritz M, Hattenhorst UE et al. (2005b). CpG island methylation and expression of tumour-associated genes in lung carcinoma. Eur J Cancer 41: 1223–1236.

    Article  CAS  Google Scholar 

  • Dunwell TL, Dickinson RE, Stankovic T, Dallol A, Weston V, Austen B et al. (2009). Frequent epigenetic inactivation of the SLIT2 gene in chronic and acute lymphocytic leukemia. Epigenetics 4: 265–269.

    Article  CAS  Google Scholar 

  • Glinsky GV, Glinskii AB, Stephenson AJ, Hoffman RM, Gerald WL . (2004). Gene expression profiling predicts clinical outcome of prostate cancer. J Clin Invest 113: 913–923.

    Article  CAS  Google Scholar 

  • Jin J, You H, Yu B, Deng Y, Tang N, Yao G et al. (2009). Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas. Biochem Biophys Res Commun 379: 86–91.

    Article  CAS  Google Scholar 

  • Kanno R, Janakiraman H, Kanno M . (2008). Epigenetic regulator polycomb group protein complexes control cell fate and cancer. Cancer Sci 99: 1077–1084.

    Article  CAS  Google Scholar 

  • Kim HK, Zhang H, Li H, Wu TT, Swisher S, He D et al. (2008). Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma. Neoplasia 10: 1411–1420.

    Article  CAS  Google Scholar 

  • Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM et al. (2006). Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125: 301–313.

    Article  CAS  Google Scholar 

  • Liu S, Shen T, Huynh L, Klisovic MI, Rush LJ, Ford JL et al. (2005). Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer Res 65: 1277–1284.

    Article  CAS  Google Scholar 

  • Mathews LA, Crea F, Farrar WL . (2009). Epigenetic gene regulation in stem cells and correlation to cancer. Differentiation 78: 1–17.

    Article  CAS  Google Scholar 

  • Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A et al. (2005). An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102: 13550–13555.

    Article  CAS  Google Scholar 

  • Oh DS, Troester MA, Usary J, Hu Z, He X, Fan C et al. (2006). Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. J Clin Oncol 24: 1656–1664.

    Article  CAS  Google Scholar 

  • Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L et al. (2007). A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39: 237–242.

    Article  CAS  Google Scholar 

  • Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P et al. (2005). Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res 7: R953–R964.

    Article  CAS  Google Scholar 

  • Prasad A, Fernandis AZ, Rao Y, Ganju RK . (2004). Slit protein-mediated inhibition of CXCR4-induced chemotactic and chemoinvasive signaling pathways in breast cancer cells. J Biol Chem 279: 9115–9124.

    Article  CAS  Google Scholar 

  • Prasad A, Paruchuri V, Preet A, Latif F, Ganju RK . (2008). Slit-2 induces a tumor-suppressive effect by regulating beta-catenin in breast cancer cells. J Biol Chem 283: 26624–26633.

    Article  CAS  Google Scholar 

  • Prasad A, Qamri Z, Wu J, Ganju RK . (2007). Slit-2/Robo-1 modulates the CXCL12/CXCR4-induced chemotaxis of T cells. J Leukoc Biol 82: 465–476.

    Article  CAS  Google Scholar 

  • Raponi M, Zhang Y, Yu J, Chen G, Lee G, Taylor JM et al. (2006). Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung. Cancer Res 66: 7466–7472.

    Article  CAS  Google Scholar 

  • Rothberg JM, Hartley DA, Walther Z, Artavanis-Tsakonas S . (1988). Slit: an EGF-homologous locus of Dmelanogaster involved in the development of the embryonic central nervous system. Cell 55: 1047–1059.

    Article  CAS  Google Scholar 

  • Sharma G, Mirza S, Prasad CP, Srivastava A, Gupta SD, Ralhan R . (2007). Promoter hypermethylation of p16INK4A, p14ARF, CyclinD2 and Slit2 in serum and tumor DNA from breast cancer patients. Life Sci 80: 1873–1881.

    Article  CAS  Google Scholar 

  • Simon JA, Kingston RE . (2009). Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 10: 697–708.

    Article  CAS  Google Scholar 

  • Simon JA, Lange CA . (2008). Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 647: 21–29.

    Article  CAS  Google Scholar 

  • Sparmann A, van Lohuizen M . (2006). Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6: 846–856.

    Article  CAS  Google Scholar 

  • Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL et al. (2007). Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 21: 1050–1063.

    Article  CAS  Google Scholar 

  • Tseng RC, Lee SH, Hsu HS, Chen BH, Tsai WC, Tzao C et al. (2010). SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis. Cancer Res 70: 543–551.

    Article  CAS  Google Scholar 

  • van ′t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M et al. (2002). Gene expression profiling predicts clinical outcome of breast cancer. Nature 415: 530–536.

    Article  Google Scholar 

  • van de Vijver MJ, He YD, van′t Veer LJ, Dai H, Hart AA, Voskuil DW et al. (2002). A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347: 1999–2009.

    Article  CAS  Google Scholar 

  • van der Vlag J, Otte AP . (1999). Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat Genet 23: 474–478.

    Article  CAS  Google Scholar 

  • Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG et al. (2002). The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419: 624–629.

    Article  CAS  Google Scholar 

  • Wang KH, Brose K, Arnott D, Kidd T, Goodman CS, Henzel W et al. (1999). Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching. Cell 96: 771–784.

    Article  CAS  Google Scholar 

  • Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F et al. (2005). Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365: 671–679.

    Article  CAS  Google Scholar 

  • Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M, Lam WL et al. (2005). Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 37: 853–862.

    Article  CAS  Google Scholar 

  • Werbowetski-Ogilvie TE, Seyed Sadr M, Jabado N, Angers-Loustau A, Agar NY, Wu J et al. (2006). Inhibition of medulloblastoma cell invasion by Slit. Oncogene 25: 5103–5112.

    Article  CAS  Google Scholar 

  • Wong K, Park HT, Wu JY, Rao Y . (2002). Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes. Curr Opin Genet Dev 12: 583–591.

    Article  CAS  Google Scholar 

  • Wu JY, Feng L, Park HT, Havlioglu N, Wen L, Tang H et al. (2001). The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410: 948–952.

    Article  CAS  Google Scholar 

  • Yu J, Cao Q, Mehra R, Laxman B, Yu J, Tomlins SA et al. (2007a). Integrative genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in prostate cancer. Cancer Cell 12: 419–431.

    Article  CAS  Google Scholar 

  • Yu J, Rhodes DR, Tomlins SA, Cao X, Chen G, Mehra R et al. (2007b). A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res 67: 10657–10663.

    Article  CAS  Google Scholar 

  • Yu YP, Landsittel D, Jing L, Nelson J, Ren B, Liu L et al. (2004). Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol 22: 2790–2799.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported in part by the NIH Prostate Specialized Program of Research Excellence Grants P50CA69568 and P50CA090386, Early Detection Research Network Grant UO1 111275 (to AMC), the NIH 1R01CA132874-01A1 (to AMC), CA114197 and CA107193 (to JYW) and K99CA129565-01A1 (to JY), the US Department of Defense PC051081 (to AMC) and PC080665 (to JY), and the James S McDonnell Foundation Grant JSMF (to JYW) and Searle Foundation (to JYW). AMC is supported by a Burroughs Welcome Foundation Award in Clinical Translational Research, a Doris Duke Charitable Foundation Distinguished Clinical Investigator Award, the Prostate Cancer Foundation and the Howard Hughes Medical Institute. AMC is an American Cancer Society Research Professor.

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Correspondence to J Yu or A M Chinnaiyan.

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AMC is a cofounder of Compendia Biosciences. Other authors declare no potential conflict of interest.

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Supplementary Information accompanies the paper on the Oncogene website

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Yu, J., Cao, Q., Yu, J. et al. The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer. Oncogene 29, 5370–5380 (2010). https://doi.org/10.1038/onc.2010.269

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