Epigallocatechin-3-gallate (EGCG), a major component of
green tea polyphenols (
GTP), has been reported to downregulate
telomerase activity in
breast cancer cells thereby increasing cellular apoptosis and inhibiting cellular proliferation. However, the major concerns with GTPs are their bioavailability and stability under physiologic conditions. In the present study, we show that treatments with EGCG and a novel
prodrug of EGCG (pro-EGCG or pEGCG) dose- and time-dependently inhibited the proliferation of human
breast cancer MCF-7 and MDA-MB-231 cells but not normal control MCF10A cells. Furthermore, both EGCG and pro-EGCG inhibited the transcription of hTERT (human
telomerase reverse transcriptase), the catalytic subunit of
telomerase, through epigenetic mechanisms in
estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells. The downregulation of hTERT expression was found to be because of hTERT promoter hypomethylation and
histone deacetylations, mediated at least partially through inhibition of
DNA methyltransferase and
histone acetyltransferase activities, respectively. In addition, we also observed that EGCG and pEGCG can remodel
chromatin structures of the hTERT promoter by decreasing the level of acetyl-H3, acetyl-H3K9, and acetyl-H4 to the hTERT promoter. EGCG and pEGCG induced
chromatin alterations that facilitated the binding of many hTERT repressors such as MAD1 and E2F-1 to the hTERT regulatory region. Depletion of E2F-1 and MAD1 by using
siRNA reversed the pEGCG downregulated hTERT expression and associated cellular apoptosis differently in ER-positive and ER-negative
breast cancer cells. Collectively, our data provide new insights into
breast cancer prevention through epigenetic modulation of
telomerase by using pro-EGCG, a more stable form of EGCG, as a novel chemopreventive compound.