Genistein depletes telomerase activity through cross-talk between genetic and epigenetic mechanisms

Authors

  • Yuanyuan Li,

    1. Department of Biology, University of Alabama at Birmingham, Birmingham, AL
    Search for more papers by this author
  • Liang Liu,

    1. Center for Aging, University of Alabama at Birmingham, Birmingham, AL
    2. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
    Search for more papers by this author
  • Lucy G. Andrews,

    1. Department of Biology, University of Alabama at Birmingham, Birmingham, AL
    Search for more papers by this author
  • Trygve O. Tollefsbol

    Corresponding author
    1. Department of Biology, University of Alabama at Birmingham, Birmingham, AL
    2. Center for Aging, University of Alabama at Birmingham, Birmingham, AL
    3. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
    4. Clinical Nutrition Research Center, University of Alabama at Birmingham, Birmingham, AL
    • CH 175, 1300 University Boulevard, Birmingham, AL, 35294-1170, USA
    Search for more papers by this author
    • Fax: +1-205-975-6097.


Abstract

Genistein, a natural isoflavone found in soybean products, has been reported to down-regulate telomerase activity and that this prevents cancer and contributes to the apoptosis of cancer cells. However, the precise molecular mechanism by which genistein represses telomerase is not clear. Here, we show that genistein inhibits the transcription of hTERT (human telomerase reverse transcriptase), the catalytic subunit of the human telomerase enzyme, in breast MCF10AT benign cells and MCF-7 cancer cells in a time- and dose-dependent manner. Three major DNA methyltransferases (DNMT1, 3a and 3b) were also decreased in genistein-treated breast cancer cells suggesting that genistein may repress hTERT by impacting epigenetic pathways. Sequential depletion of the hTERT promoter revealed that the hTERT core promoter region is responsible for the genistein-induced repression of hTERT transcription. Using a newly developed technique of chromatin immunoprecipitation (ChIP)-related bifulfite sequencing analysis, we found an increased binding of E2F-1 to the hTERT promoter is due to the site-specific hypomethylation of the E2F-1 recognition site. In addition, we found that genistein can remodel chromatin structures of the hTERT promoter by increasing trimethyl-H3K9 but decreasing dimethyl-H3K4 in the hTERT promoter. The repression of hTERT was enhanced by combination with genistein and the DNMT inhibitor, 5-aza-2′-deoxycytidine (5-aza-dCyd). These findings collectively show that genistein is working, at least in part, through epigenetic mechanisms of telomerase inhibition in breast benign and cancer cells and may facilitate approaches to breast cancer prevention and treatment using an epigenetic modulator combined with genistein. © 2009 UICC

Ancillary