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Triptolide Inhibits Histone Methyltransferase EZH2 and Modulates the Expression of Its Target Genes in Prostate Cancer Cells

  • Tamgue, Ousman (Key Laboratory of Agricultural Molecular Biology, College of Life Science, Northwest A&F University) ;
  • Chai, Cheng-Sen (Key Laboratory of Agricultural Molecular Biology, College of Life Science, Northwest A&F University) ;
  • Hao, Lin (Key Laboratory of Agricultural Molecular Biology, College of Life Science, Northwest A&F University) ;
  • Zambe, John-Clotaire Daguia (Key Laboratory of Agricultural Molecular Biology, College of Life Science, Northwest A&F University) ;
  • Huang, Wei-Wei (Key Laboratory of Agricultural Molecular Biology, College of Life Science, Northwest A&F University) ;
  • Zhang, Bin (Key Laboratory of Agricultural Molecular Biology, College of Life Science, Northwest A&F University) ;
  • Lei, Ming (Key Laboratory of Agricultural Molecular Biology, College of Life Science, Northwest A&F University) ;
  • Wei, Yan-Ming (Key Laboratory of Agricultural Molecular Biology, College of Life Science, Northwest A&F University)
  • Published : 2013.10.30

Abstract

The histone methyltransferase EZH2 (enhancer of zeste homolog 2) plays critical roles in prostate cancer (PCa) development and is a potential target for PCa treatment. Triptolide possesses anti-tumor activity, but it is unknown whether its therapeutic effect relates with EZH2 in PCa. Here we described EZH2 as a target for Triptolide in PCa cells. Our data showed that Triptolide suppressed PCa cell growth and reduced the expression of EZH2. Overexpression of EZH2 attenuated the Triptolide induced cell growth inhibition. Moreover, Triptolide treatment of PC-3 cells resulted in elevated mRNA levels of target genes (ADRB2, CDH1, CDKN2A and DAB2IP) negatively regulated by EZH2 as well as reduced mRNA levelsan of EZH2 positively regulated gene (cyclin D1). Our findings suggest the PCa cell growth inhibition mediated by Triptolide might be associated with downregulation of EZH2 expression and the subsequent modulation of target genes.

Keywords

EZH2;EZH2 target genes;prostate cancer (PCa);Triptolide

References

  1. Crea F, Hurt EM, Mathews LA, et al (2011). Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol Cancer, 10, 40. https://doi.org/10.1186/1476-4598-10-40
  2. Antonoff MB, Chugh R, Borja-Cacho D, et al (2009). Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo. Surgery, 146, 282-90. https://doi.org/10.1016/j.surg.2009.04.023
  3. Cao Q, Yu J, Dhanasekaran SM, et al (2008). Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene, 27, 7274-84. https://doi.org/10.1038/onc.2008.333
  4. Chang CJ, Hung MC (2012). The role of EZH2 in tumour progression. Br J Cancer, 106, 243-7. https://doi.org/10.1038/bjc.2011.551
  5. Chase A, Cross NC (2011). Aberrations of EZH2 in Cancer. Clin Cancer Res, 17, 2613-8. https://doi.org/10.1158/1078-0432.CCR-10-2156
  6. Ellis L, Atadja PW, Johnstone RW (2009). Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther, 8, 1409-20.
  7. Etchegaray JP, Yang X, DeBruyne JP, et al (2006). The polycomb group protein EZH2 is required for mammalian circadian clock function. J Biol Chem, 281, 21209-15. https://doi.org/10.1074/jbc.M603722200
  8. Feldman BJ, Feldman D (2001). The development of androgen-independent prostate cancer. Nat Rev Cancer, 1, 34-45. https://doi.org/10.1038/35094009
  9. Fussbroich B, Wagener N, Macher-Goeppinger S, et al (2011). EZH2 depletion blocks the proliferation of colon cancer cells. PLoS One, 6, e21651. https://doi.org/10.1371/journal.pone.0021651
  10. Gil J, Bernard D, Peters G (2005). Role of polycomb group proteins in stem cell self-renewal and cancer. DNA Cell Biol, 24, 117-25. https://doi.org/10.1089/dna.2005.24.117
  11. Kiviharju TM, Lecane PS, Sellers RG, et al (2002). Antiproliferative and proapoptotic activities of triptolide (PG490), a natural product entering clinical trials, on primary cultures of human prostatic epithelial cells. Clin Cancer Res, 8, 2666-74.
  12. Huang W, He T, Chai C, et al (2012). Triptolide inhibits the proliferation of prostate cancer cells and down-regulates SUMO-specific protease 1 expression. PLoS One, 7, e37693. https://doi.org/10.1371/journal.pone.0037693
  13. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  14. Kamminga LM, Bystrykh LV, de Boer A, et al (2006). The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood, 107, 2170-9. https://doi.org/10.1182/blood-2005-09-3585
  15. Liu J, Jiang Z, Xiao J, et al (2009). Effects of triptolide from Tripterygium wilfordii on ERalpha and p53 expression in two human breast cancer cell lines. Phytomedicine, 16, 1006-13. https://doi.org/10.1016/j.phymed.2009.03.021
  16. Min J, Zaslavsky A, Fedele G, et al (2010). An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat Med, 16, 286-94. https://doi.org/10.1038/nm.2100
  17. O'Carroll D, Erhardt S, Pagani M, et al (2001). The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol, 21, 4330-6. https://doi.org/10.1128/MCB.21.13.4330-4336.2001
  18. Phillips PA, Dudeja V, McCarroll JA, et al (2007). Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res, 67, 9407-16. https://doi.org/10.1158/0008-5472.CAN-07-1077
  19. Plath K, Fang J, Mlynarczyk-Evans SK, et al (2003). Role of histone H3 lysine 27 methylation in X inactivation. Science, 300, 131-5. https://doi.org/10.1126/science.1084274
  20. Ren SC, Chen R, Sun YH (2013). Prostate cancer research in China. Asian J Androl, 15, 350-3. https://doi.org/10.1038/aja.2013.37
  21. Shi B, Liang J, Yang X, et al (2007). Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol, 27, 5105-19. https://doi.org/10.1128/MCB.00162-07
  22. Saramaki OR, Tammela TL, Martikainen PM, et al (2006). The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancer. Genes Chromosomes Cancer, 45, 639-45. https://doi.org/10.1002/gcc.20327
  23. Sauvageau M, Sauvageau G (2010). Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell, 7, 299-313. https://doi.org/10.1016/j.stem.2010.08.002
  24. Schulz WA, Hatina J (2006). Epigenetics of prostate cancer: beyond DNA methylation. J Cell Mol Med, 10, 100-25. https://doi.org/10.1111/j.1582-4934.2006.tb00293.x
  25. Su IH, Basavaraj A, Krutchinsky AN, et al (2003). Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol, 4, 124-31. https://doi.org/10.1038/ni876
  26. Su IH, Dobenecker MW, Dickinson E, et al (2005). Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell, 121, 425-36. https://doi.org/10.1016/j.cell.2005.02.029
  27. Titov DV, Gilman B, He QL, et al (2011). XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol, 7, 182-8. https://doi.org/10.1038/nchembio.522
  28. Varambally S, Dhanasekaran SM, Zhou M, et al (2002). The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature, 419, 624-9. https://doi.org/10.1038/nature01075
  29. Wang Y, Lu JJ, He L, et al (2011). Triptolide (TPL) inhibits global transcription by inducing proteasome-dependent degradation of RNA polymerase II (Pol II). PLoS One, 6, e23993. https://doi.org/10.1371/journal.pone.0023993
  30. Wang Z, Jin H, Xu R, et al (2009). Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression. Exp Mol Med, 41, 717-27. https://doi.org/10.3858/emm.2009.41.10.078
  31. Yu J, Yu J, Mani RS, et al (2010). An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell, 17, 443-54. https://doi.org/10.1016/j.ccr.2010.03.018
  32. Westerheide SD, Kawahara TL, Orton K, et al (2006). Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death. J Biol Chem, 281, 9616-22. https://doi.org/10.1074/jbc.M512044200
  33. Wu SC, Zhang Y (2011). Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of enhancer of zeste 2 (Ezh2) regulates its stability. J Biol Chem, 286, 28511-9. https://doi.org/10.1074/jbc.M111.240515
  34. Yu J, Cao Q, Mehra R, et al (2007). Integrative genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in prostate cancer. Cancer Cell, 12, 419-31. https://doi.org/10.1016/j.ccr.2007.10.016
  35. Zhao F, Chen Y, Zeng L, et al (2010). Role of triptolide in cell proliferation, cell cycle arrest, apoptosis and histone methylation in multiple myeloma U266 cells. Eur J Pharmacol, 646, 1-11. https://doi.org/10.1016/j.ejphar.2010.05.034
  36. Zhao F, Chen Y, Li R, et al (2010). Triptolide alters histone H3K9 and H3K27 methylation state and induces G0/G1 arrest and caspase-dependent apoptosis in multiple myeloma in vitro. Toxicology, 267, 70-9. https://doi.org/10.1016/j.tox.2009.10.023
  37. Zhu W, Ou Y, Li Y, et al (2009). A small-molecule triptolide suppresses angiogenesis and invasion of human anaplastic thyroid carcinoma cells via down-regulation of the nuclear factor-kappa B pathway. Mol Pharmacol, 75, 812-9. https://doi.org/10.1124/mol.108.052605

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