DOI QR코드

DOI QR Code

Garcinol, an Acetyltransferase Inhibitor, Suppresses Proliferation of Breast Cancer Cell Line MCF-7 Promoted by 17β-Estradiol

  • Ye, Xia (Department of Pathophysiology, School of Basic Medicine, Chongqing Medical University) ;
  • Yuan, Lei (Department of Pathophysiology, School of Basic Medicine, Chongqing Medical University) ;
  • Zhang, Li (Department of Pathophysiology, School of Basic Medicine, Chongqing Medical University) ;
  • Zhao, Jing (Department of Pathophysiology, School of Basic Medicine, Chongqing Medical University) ;
  • Zhang, Chun-Mei (Department of Pathophysiology, School of Basic Medicine, Chongqing Medical University) ;
  • Deng, Hua-Yu (Department of Pathophysiology, School of Basic Medicine, Chongqing Medical University)
  • Published : 2014.06.30

Abstract

The acetyltransferase inhibitor garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Anti-cancer activity has been suggested but there is no report on its action via inhibiting acetylation against cell proliferation, cell cycle progression, and apoptosis-inhibtion induced by estradiol ($E_2$) in human breast cancer MCF-7 cells. The main purposes of this study were to investigate the effects of the acetyltransferase inhibitor garcinol on cell proliferation, cell cycle progression and apoptosis inhibition in human breast cancer MCF-7 cells treated with estrogen, and to explore the significance of changes in acetylation levels in this process. We used a variety of techniques such as CCK-8 analysis of cell proliferation, FCM analysis of cell cycling and apoptosis, immunofluorescence analysis of NF-${\kappa}B$/p65 localization, and RT-PCR and Western blotting analysis of ac-H3, ac-H4, ac-p65, cyclin D1, Bcl-2 and Bcl-xl. We found that on treatment with garcinol in MCF-7 cells, $E_2$-induced proliferation was inhibited, cell cycle progression was arrested at G0/G1 phase, and the cell apoptosis rate was increased. Expression of ac-H3, ac-H4 and NF-${\kappa}B$/ac-p65 proteins in $E_2$-treated MCF-7 cells was increased, this being inhibited by garcinol but not ac-H4.The nuclear translocation of NF-${\kappa}B$/p65 in $E_2$-treated MCF-7 cells was also inhibited, along with cyclin D1, Bcl-2 and Bcl-xl in mRNA and protein expression levels. These results suggest that the effect of $E_2$ on promoting proliferation and inhibiting apoptosis is linked to hyperacetylation levels of histones and nonhistone NF-${\kappa}B$/p65 in MCF-7 cells. The acetyltransferase inhibitor garcinol plays an inhibitive role in MCF-7 cell proliferation promoted by $E_2$. Mechanisms are probably associated with decreasing ac-p65 protein expression level in the NF-${\kappa}B$ pathway, thus down-regulating the expression of cyclin D1, Bcl-2 and Bcl-xl.

Acknowledgement

Supported by : National Natural Science Foundation of China

References

  1. Jemal A, Siegel R, Ward E, et al (2009). Cancer statistics, 2009. CA Cancer J Clin, 59, 225-49. https://doi.org/10.3322/caac.20006
  2. Jin W, Chen L, ChenY, et al (2010). UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer. Breast Cancer Res Treat, 123, 359-73. https://doi.org/10.1007/s10549-009-0652-2
  3. Jin W, Liu Y, Chen L, et al (2011). Involvement of MyoD and c-myb in regulation of basal and estrogen-induced transcription activity of the BRCA1 gene. Breast Cancer Res Treat, 125, 699-713. https://doi.org/10.1007/s10549-010-0876-1
  4. Jana D, Das S, Sarkar DK, et al (2012). Role of nuclear factor-$\kappa{B}$ in female breast cancer: a study in Indian patients. Asian Pac J Cancer Prev, 13, 5511-5. https://doi.org/10.7314/APJCP.2012.13.11.5511
  5. Kininis M, Chen BS, Diehl AG, et al (2007). Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters. Mol Cell Biol, 27, 5090-104. https://doi.org/10.1128/MCB.00083-07
  6. Kutanzi KR, Koturbash I, Kovalchuk O (2010). Reversibility of pre-malignant estrogen-induced epigenetic changes. Cell Cycle, 9, 3078-84.
  7. Kim JW, Jang SM, Kim CH, et al (2012). New molecular bridge between RelA/p65 and NF-kappaB target genes via histone acetyltransferase TIP60 cofactor. J Biol Chem, 287, 7780-91. https://doi.org/10.1074/jbc.M111.278465
  8. Khan ZN, Sabir M, Kayani MA, et al (2013). Acetylation of retinoblastoma like protein2 (Rb2/p130) in tumor tissues. Asian Pac J Cancer Prev, 14, 2255-8. https://doi.org/10.7314/APJCP.2013.14.3.2255
  9. Lee DY, Hayes JJ, Pruss D, et al (1993). A positive role for histone acetylation in transcription factor access to nucleosomal DNA. Cell, 72, 73-84. https://doi.org/10.1016/0092-8674(93)90051-Q
  10. Minatoya M, Kutomi G, Asakura S, et al (2013). Equol, adiponectin, insulin levels and risk of breast cancer. Asian Pac J Cancer Prev, 14, 2191-9. https://doi.org/10.7314/APJCP.2013.14.4.2191
  11. Chen LF, Mu Y, Greene WC (2002). Acetylation of RelA at discrete sites regulates distinct nuclear functions of NFkappaB. EMBO J, 21, 6539-48. https://doi.org/10.1093/emboj/cdf660
  12. Zubair A, Frieri M (2013). Role of nuclear factor-kB in breast and colorectal cancer. Curr Allergy Asthma Rep, 13, 44-9. https://doi.org/10.1007/s11882-012-0300-5
  13. Arif M, Pradhan SK, Thanuja GR, et al (2009). Mechanism of p300 specific histone acetyltransferase inhibition by small molecules. J Med Chem, 52, 267-77. https://doi.org/10.1021/jm800657z
  14. Balasubramanyam K, Altaf M, Varier RA, et al (2004). Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J Biol Chem, 279, 33716-26. https://doi.org/10.1074/jbc.M402839200
  15. Baumgarten SC, Frasor J (2012). Minireview: Inflammation: an instigator of more aggressive estrogen receptor (ER) positive breast cancers. Mol Endocrinol, 26, 360-71. https://doi.org/10.1210/me.2011-1302
  16. Chen H, Ln RJ, Xie W, et al (1999). Regulation of hormoneinduced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell, 98, 675-86. https://doi.org/10.1016/S0092-8674(00)80054-9
  17. Dhalluin C, Carlson JE, Zeng L, et al (1999). Structure and ligand of a histone acetyltransferase bromodomain. Nature, 399, 491-6. https://doi.org/10.1038/20974
  18. Dicerbo V, Schneider R (2013). Cancers with wrong HATs: the impact of acetylation. Brief Funct Genomics, 12, 231-43. https://doi.org/10.1093/bfgp/els065
  19. Han D, Denison MS, Tachibana H, et al (2002). Effects of estrogenic compounds on immunoglobulin production by mouse splenocytes. Biol Pharm Bull, 25, 1263-7. https://doi.org/10.1248/bpb.25.1263
  20. Iiuzka M, Takahashi Y, Mizzen CA, et al (2009). Histone acetyltransferase Hbo1: catalytic activity, cellular abundance, and links to primary cancers. Gene, 436, 108-14. https://doi.org/10.1016/j.gene.2009.01.020
  21. Rubio MF, Werbajh S, Cafferatae G, et al (2006). TNF-alpha enhances estrogen-induced cell proliferation of estrogendependent breast tumor cells through a complex containing nuclear factor-kappa B. Oncogene, 25, 1367-77. https://doi.org/10.1038/sj.onc.1209176
  22. Marmorstein R, Trievel RC (2009). Histone modifying enzymes: structures, mechanisms, and specificities. Biochim Biophys Acta, 1789, 58-68. https://doi.org/10.1016/j.bbagrm.2008.07.009
  23. Pradhan M, Baumgarten SC, Bembinster LA, et al (2012). CBP mediates NF-kappaB-dependent histone acetylation and estrogen receptor recruitment to an estrogen response element in the BIRC3 promoter. Mol Cell Biol, 32, 569-75. https://doi.org/10.1128/MCB.05869-11
  24. Quivy V, Van Lint C (2004). Regulation at multiple levels of NF-kappaB-mediated transactivation by protein acetylation. Biochem Pharmacol, 68, 1221-9. https://doi.org/10.1016/j.bcp.2004.05.039
  25. Singh BN, Zhang G, Hwa YL, et al (2010). Nonhistone protein acetylation as cancer therapy targets. Expert Rev Anticancer Ther, 10, 935-54. https://doi.org/10.1586/era.10.62
  26. Sung B, Pandey MK, Ahn KS, et al (2008). Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-kappaB-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-kappaBalpha kinase, leading to potentiation of apoptosis. Blood, 111, 4880-91. https://doi.org/10.1182/blood-2007-10-117994
  27. Saadat N, Gupta SV (2012). Potential role of garcinol as an anticancer agent. J Oncol, 2012, 647206.
  28. Wang GG, Allis CD, Chi P (2007). Chromatin remodeling and cancer, Part I: Covalent histone modifications. Trends Mol Med, 13, 363-72. https://doi.org/10.1016/j.molmed.2007.07.003
  29. Zhang CM, Zhao J, Deng HY (2013). 17beta-estradiol upregulates miR-155 expression and reduces TP53INP1 expression in MCF-7 breast cancer cells. Mol Cell Biochem, 379, 201-11. https://doi.org/10.1007/s11010-013-1642-6
  30. Mooney SM, Goel A, D'assoro AB, et al (2010). Pleiotropic effects of p300-mediated acetylation on p68 and p72 RNA helicase. J Biol Chem, 285, 30443-52. https://doi.org/10.1074/jbc.M110.143792

Cited by

  1. KATs in cancer: functions and therapies vol.34, pp.38, 2015, https://doi.org/10.1038/onc.2014.453
  2. HAT inhibitor, garcinol, exacerbates lipopolysaccharide-induced inflammation in vitro and in vivo vol.13, pp.6, 2016, https://doi.org/10.3892/mmr.2016.5189
  3. Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-κB inhibition in oral cancer vol.37, pp.6, 2016, https://doi.org/10.1007/s13277-015-4583-8
  4. The bounty of nature for changing the cancer landscape vol.60, pp.6, 2016, https://doi.org/10.1002/mnfr.201500867
  5. Histone acetyltransferases: challenges in targeting bi-substrate enzymes vol.8, pp.1, 2016, https://doi.org/10.1186/s13148-016-0225-2
  6. Garcinol exhibits anti-proliferative activities by targeting microsomal prostaglandin E synthase-1 in human colon cancer cells vol.36, pp.7, 2017, https://doi.org/10.1177/0960327116660865
  7. Garcinol downregulates Notch1 signaling via modulating miR-200c and suppresses oncogenic properties of PANC-1 cancer stem-like cells vol.64, pp.2, 2017, https://doi.org/10.1002/bab.1446
  8. and NF-κB/Twist1 signaling pathways in a mouse 4T1 breast tumor model vol.8, pp.3, 2017, https://doi.org/10.1039/C6FO01588C
  9. Chronic diseases, inflammation, and spices: how are they linked? vol.16, pp.1, 2018, https://doi.org/10.1186/s12967-018-1381-2
  10. The Histone Acetylation Modifications of Breast Cancer and their Therapeutic Implications vol.24, pp.4, 2018, https://doi.org/10.1007/s12253-018-0433-5
  11. Effects of RNA interference-mediated silencing of toll-like receptor 4 gene on proliferation and apoptosis of human breast cancer MCF-7 and MDA-MB-231 cells: An in vitro study pp.00219541, 2018, https://doi.org/10.1002/jcp.26573