Epidemiologic studies have revealed that diets rich in
sulforaphane (SFN), an
isothiocyanate present in cruciferous vegetables, are associated with a marked decrease in
prostate cancer incidence. The chemo-preventive role of SFN is associated with its
histone de-
acetylase inhibitor activity. However, the effect of SFN on
chromatin composition and dynamic folding, especially in relation to
HDAC inhibitor activity, remains poorly understood. In this study, we found that SFN can inhibit the expression and activity of human
telomerase reverse transcriptase (hTERT), the catalytic subunit of
telomerase, in 2
prostate cancer cell lines. This decrease in gene expression is correlated with SFN-induced changes in
chromatin structure and composition. The SFN-mediated changes in levels of
histone post-translational modifications, more specifically acetylation of
histone H3 lysine 18 and di-methylation of
histone H3 lysine 4, 2 modifications linked with high risk of
prostate cancer recurrence, were associated with regulatory elements within the hTERT promoter region.
Chromatin condensation may also play a role in SFN-mediated hTERT repression, since expression and recruitment of MeCP2, a known
chromatin compactor, were altered in SFN treated
prostate cancer cells.
Chromatin immuno-precipitation (ChIP) of MeCP2 showed enrichment over regions of the hTERT promoter with increased
nucleosome density. These combined results strongly support a role for SFN in the mediation of epigenetic events leading to the repression of hTERT in
prostate cancer cells. This ability of SFN to modify
chromatin composition and structure associated with target gene expression provides a new model by which
dietary phytochemicals may exert their
chemoprevention activity.