Green tea is widely consumed as a popular beverage worldwide and has chemopreventive and anticancer properties. A major constituent of green tea is the polyphenol, (-)-epigallocatechin-3-gallate (EGCG), that is effective in the prevention of breast cancer, a leading cause of cancer-related deaths among females in the United States. Many studies have indicated that EGCG inhibits DNA methyltransferase 1 and telomerase activity which play critical roles in the progression of tumorigenesis. Telomerase inhibition by EGCG leads to apoptosis of cancer cells and oral administration of EGCG is effective especially in telomerase-expressing cancer cells. We discovered that EGCG down-regulates telomerase primarily through transcriptional control of the telomerase regulatory gene, hTERT, and other laboratories have now reported similar findings. Alterations of the hTERT gene by green tea polyphenols involve changes in histone acetylation, DNA methylation, and transcription factor binding although the roles of other epigenetic processes and the in vivo mechanisms are not fully understood. The main hypothesis is that green tea polyphenols prevent the epigenetic processes that lead to telomerase activation in breast cancer. A secondary hypothesis is that green tea modulates the availability of the histone deacetylases (HDACs), histone methyltransferases (HMTases) and/or DNA methyltransferases (DNMTs) as well as key transcription factors to the hTERT promoter leading to breast cancer prevention.
Aim 1 will assess the role of green tea polyphenols in controlling histone methylation and acetylation at key residues known to be involved in hTERT regulation.
Aim 2 will evaluate the interactions of the hTERT promoter with key epigenetic modulators such as the HDACs, HMTases and DNMTs as well as major transcriptional regulators of hTERT.
Aim 3 is to measure the in vivo effects of green tea polyphenols on epigenetic processes controlling the hTERT promoter using breast preclinical cancer prevention models. Since green tea has promise in reducing the incidence of breast cancer, the goal of this proposal is to determine the epigenetic mechanisms, both in vitro and in vivo, whereby this common dietary component decreases the incidence of breast cancer. It is intended that the outcome of these studies will facilitate more effective uses of green tea and/or polyphenols in cancer prevention and will help elucidate the mechanisms through which green tea imparts its chemopreventive properties.

Public Health Relevance

: Chemotherapy of cancer patients often produces unsatisfactory and/or toxic effects. Investigations into non-toxic or less cytotoxic modes of cancer prevention or treatment are therefore warranted. The proposed studies will help elucidate how dietary green tea imparts its chemopreventive and anticancer effects and may lead to novel approaches to cancer prevention through control not only of dietary factors, but also through epigenetic processes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129415-03
Application #
7762249
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Ross, Sharon A
Project Start
2008-04-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
3
Fiscal Year
2010
Total Cost
$240,700
Indirect Cost
Name
University of Alabama Birmingham
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Martin, Samantha L; Kala, Rishabh; Tollefsbol, Trygve O (2017) Mechanisms for inhibition of colon cancer cells by sulforaphane through epigenetic modulation of microRNA-21 and human telomerase reverse transcriptase (hTERT) down-regulation. Curr Cancer Drug Targets :
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Saldanha, Sabita N; Kala, Rishabh; Tollefsbol, Trygve O (2014) Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate. Exp Cell Res 324:40-53
Li, Yuanyuan; Tollefsbol, Trygve O (2013) Analysis of biomarkers of caloric restriction in aging cells. Methods Mol Biol 1048:19-29
Chen, Huaping; Li, Yuanyuan; Tollefsbol, Trygve O (2013) Cell senescence culturing methods. Methods Mol Biol 1048:1-10
Li, Yuanyuan; Meeran, Syed M; Patel, Shweta N et al. (2013) Epigenetic reactivation of estrogen receptor-? (ER?) by genistein enhances hormonal therapy sensitivity in ER?-negative breast cancer. Mol Cancer 12:9
Chen, Huaping; Landen, Charles N; Li, Yuanyuan et al. (2013) Enhancement of Cisplatin-Mediated Apoptosis in Ovarian Cancer Cells through Potentiating G2/M Arrest and p21 Upregulation by Combinatorial Epigallocatechin Gallate and Sulforaphane. J Oncol 2013:872957
Martin, S L; Hardy, T M; Tollefsbol, T O (2013) Medicinal chemistry of the epigenetic diet and caloric restriction. Curr Med Chem 20:4050-9

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