DOI QR코드

DOI QR Code

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

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  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. 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
  12. 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
  13. 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
  14. 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.
  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. 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
  22. 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
  23. 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
  24. 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
  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. 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
  32. 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
  33. 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
  34. 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
  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

Cited by

  1. Roles of E-Cadherin (CDH1) Genetic Variations in Cancer Risk: a Meta-analysis vol.15, pp.8, 2014, https://doi.org/10.7314/APJCP.2014.15.8.3705
  2. Mechanistic Studies of Cyclin-Dependent Kinase Inhibitor 3 (CDKN3) in Colorectal Cancer vol.16, pp.3, 2015, https://doi.org/10.7314/APJCP.2015.16.3.965
  3. Toosendanin inhibits growth and induces apoptosis in colorectal cancer cells through suppression of AKT/GSK-3β/β-catenin pathway vol.47, pp.5, 2015, https://doi.org/10.3892/ijo.2015.3157
  4. Design, synthesis and biological evaluation of novel 1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolins as potential EZH2 inhibitors vol.5, pp.33, 2015, https://doi.org/10.1039/C5RA02365C
  5. The CDH1 -160C/A polymorphism is associated with breast cancer: evidence from a meta-analysis vol.14, pp.1, 2016, https://doi.org/10.1186/s12957-016-0927-0
  6. Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants vol.77, pp.6, 2017, https://doi.org/10.1002/pros.23298
  7. Triptolide inhibits Wnt signaling in NSCLC through upregulation of multiple Wnt inhibitory factors via epigenetic modifications to Histone H3 vol.143, pp.10, 2018, https://doi.org/10.1002/ijc.31756
  8. Triptolide, A Potential Autophagy Modulator pp.1993-0402, 2018, https://doi.org/10.1007/s11655-018-2847-z
  9. Synthesis and biological evaluation of benzomorpholine derivatives as novel EZH2 inhibitors for anti-non-small cell lung cancer activity pp.1573-501X, 2019, https://doi.org/10.1007/s11030-018-9903-7