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The polycomb group protein EZH2 is involved in progression of prostate cancer

Abstract

Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling1, that the polycomb group protein enhancer of zeste homolog 2 (EZH2)2,3 is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes4 targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.

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Figure 1: Overexpression of EZH2 in metastatic hormone-refractory prostate cancer (MET).
Figure 2: Amounts of EZH2 protein correlate with the aggressiveness of prostate cancer.
Figure 3: A role for EZH2 in prostate cell proliferation.
Figure 4: EZH2 functions as a transcriptional repressor in prostate cells.

References

  1. Dhanasekaran, S. M. et al. Delineation of prognostic biomarkers in prostate cancer. Nature 412, 822–826 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Laible, G. et al. Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres. EMBO J. 16, 3219–3232 (1997)

    Article  CAS  Google Scholar 

  3. Satijn, D. P. & Otte, A. P. Polycomb group protein complexes: do different complexes regulate distinct target genes? Biochim. Biophys. Acta 1447, 1–16 (1999)

    Article  CAS  Google Scholar 

  4. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001)

    Article  ADS  CAS  Google Scholar 

  5. Jacobs, J. J. & van Lohuizen, M. Cellular memory of transcriptional states by Polycomb-group proteins. Semin. Cell. Dev. Biol. 10, 227–235 (1999)

    Article  CAS  Google Scholar 

  6. Francis, N. J. & Kingston, R. E. Mechanisms of transcriptional memory. Nature Rev. Mol. Cell Biol. 2, 409–421 (2001)

    Article  CAS  Google Scholar 

  7. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999)

    Article  ADS  CAS  Google Scholar 

  8. Jacobs, J. J. et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13, 2678–2690 (1999)

    Article  CAS  Google Scholar 

  9. Mahmoudi, T. & Verrijzer, C. P. Chromatin silencing and activation by Polycomb and trithorax group proteins. Oncogene 20, 3055–3066 (2001)

    Article  CAS  Google Scholar 

  10. LaJeunesse, D. & Shearn, A. E(z): a polycomb group gene or a trithorax group gene? Development 122, 2189–2197 (1996)

    CAS  PubMed  Google Scholar 

  11. Raaphorst, F. M. et al. Coexpression of BMI-1 and EZH2 polycomb group genes in Reed-Sternberg cells of Hodgkin's disease. Am. J. Pathol. 157, 709–715 (2000)

    Article  CAS  Google Scholar 

  12. van Lohuizen, M. et al. Identification of cooperating oncogenes in Eµ–myc transgenic mice by provirus tagging. Cell 65, 737–752 (1991)

    Article  CAS  Google Scholar 

  13. Haupt, Y., Alexander, W. S., Barri, G., Klinken, S. P. & Adams, J. M. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in Eµ–myc transgenic mice. Cell 65, 753–763 (1991)

    Article  CAS  Google Scholar 

  14. Jenuwein, T., Laible, G., Dorn, R. & Reuter, G. SET domain proteins modulate chromatin domains in eu- and heterochromatin. Cell. Mol. Life Sci. 54, 80–93 (1998)

    Article  CAS  Google Scholar 

  15. Tusher, V. G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001)

    Article  ADS  CAS  Google Scholar 

  16. van Lohuizen, M. et al. Interaction of mouse polycomb-group (Pc-G) proteins Enx1 and Enx2 with Eed: indication for separate Pc-G complexes. Mol. Cell. Biol. 18, 3572–3579 (1998)

    Article  CAS  Google Scholar 

  17. Sewalt, R. G. et al. Characterization of interactions between the mammalian polycomb-group proteins Enx1/EZH2 and EED suggests the existence of different mammalian polycomb-group protein complexes. Mol. Cell. Biol. 18, 3586–3595 (1998)

    Article  CAS  Google Scholar 

  18. Rubin, M. A. et al. Rapid (‘warm’) autopsy study for procurement of metastatic prostate cancer. Clin. Cancer Res. 6, 1038–1045 (2000)

    CAS  PubMed  Google Scholar 

  19. Perrone, E. E. et al. Tissue microarray assessment of prostate cancer tumour proliferation in African-American and white men. J. Natl Cancer Inst. 92, 937–939 (2000)

    Article  CAS  Google Scholar 

  20. Webber, M. M., Bello, D., Kleinman, H. K. & Hoffman, M. P. Acinar differentiation by non-malignant immortalized human prostatic epithelial cells and its loss by malignant cells. Carcinogenesis 18, 1225–1231 (1997)

    Article  CAS  Google Scholar 

  21. Bello, D., Webber, M. M., Kleinman, H. K., Wartinger, D. D. & Rhim, J. S. Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. Carcinogenesis 18, 1215–1223 (1997)

    Article  CAS  Google Scholar 

  22. Littlewood, T. D., Hancock, D. C., Danielian, P. S., Parker, M. G. & Evan, G. I. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. Nucleic Acids Res. 23, 1686–1690 (1995)

    Article  CAS  Google Scholar 

  23. Juin, P., Hueber, A. O., Littlewood, T. & Evan, G. c-Myc induced sensitization to apoptosis is mediated through cytochrome c release. Genes Dev. 13, 1367–1381 (1999)

    Article  CAS  Google Scholar 

  24. van der Vlag, J. & Otte, A. P. Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nature Genet. 23, 474–478 (1999)

    Article  CAS  Google Scholar 

  25. Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)

    Article  ADS  CAS  Google Scholar 

  26. Manley, S., Mucci, N. R., De Marzo, A. M. & Rubin, M. A. Relational database structure to manage high-density tissue microarray data and images for pathology studies focusing on clinical outcome: the prostate specialized program of research excellence model. Am. J. Pathol. 159, 837–843 (2001)

    Article  CAS  Google Scholar 

  27. Bova, G. S. et al. Web-based tissue microarray image data analysis: initial validation testing through prostate cancer Gleason grading. Hum. Pathol. 32, 417–427 (2001)

    Article  CAS  Google Scholar 

  28. Kumar-Sinha, C., Varambally, S., Sreekumar, A. & Chinnaiyan, A. M. Molecular cross-talk between the TRAIL and interferon signaling pathways. J. Biol. Chem. 277, 575–585 (2001)

    Article  Google Scholar 

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Acknowledgements

This study was made possible by tissues donated by patients with metastatic prostate cancer enrolled in the University of Michigan, Rapid Autopsy Program funded by the Specialized Program of Research Excellence (SPORE) in Prostate Cancer at the National Cancer Institute. We thank J. Wei for clinical data collection; K. Hamer for preparing polycomb antibodies; R. Kunkel for figure preparation; J. Harwood and M. LeBlanc for technical assistance; A. Menon for sequence verification; and C. Ingold and G. Tueckmantel for database assistance. A.M.C. is a Pew Foundation Scholar. This work is supported in part by grants from the NIH (A.M.C.), CaPCURE (A.M.C.) and the Michigan SPORE in Prostate Cancer (K.P., M.A.R., A.M.C. and M.G.S.).

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Correspondence to Arul M. Chinnaiyan.

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Varambally, S., Dhanasekaran, S., Zhou, M. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002). https://doi.org/10.1038/nature01075

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