Targeting the epigenome, including the use of histone deacetylase (HDAC)
inhibitors, is a novel strategy for cancer chemoprevention. Sulforaphane
(SFN), a compound found at high levels in broccoli and broccoli sprouts, is a
potent inducer of Phase 2 detoxification enzymes and inhibits tumorigenesis
in animal models. SFN also has a marked effect on cell cycle checkpoint
controls and cell survival/apoptosis in various cancer cells, through
mechanisms that are poorly understood. Based on the structure of known
histone deacetylase inhibitors, it was hypothesized that SFN may possess
HDAC inhibitory properties. Initial studies confirmed that, indeed, at
physiologically-relevant concentrations, SFN inhibited HDAC activity in
human colorectal cancer cells, with a concomitant increase in acetylated
histones H3 and H4, induction of p21 expression, and increased acetylated
histone H4 associated with the P21 promoter. A metabolite of SFN, SFN-Cysteine,
was found to be the active HDAC inhibitor. Furthermore, in BPH-1,
LnCaP, and PC-3 human prostate epithelial cells, SFN inhibited HDAC
activity and increased acetylation of histones. SFN also induced p21
expression, with an increase in acetylated histone H4 associated with the P21
promoter in BPH-1 cells. The downstream effects of HDAC inhibition by SFN
included induction of pro-apoptotic proteins and repression of anti-apoptotic
proteins, and an increase in multi-caspase activity. Dietary SFN suppressed
the growth of human prostate cancer PC-3 xenografts and inhibited HDAC
activity in the xenografts, peripheral blood mononuclear cells (PBMC), and
prostates. In time-course studies, a single oral dose of SFN induced histone
acetylation at 6 and 24 h in mouse colonic mucosa, and long-term dietary
SFN treatment increased histone acetylation in the ileum, colon, PBMC, and
prostates. Moreover, dietary SFN suppressed intestinal tumorigenesis
significantly in Apc[superscrip min] mice, with an increase in acetylated histones detected
in the normal-looking ileum and polyps and polyps from the colon. Overall,
the data presented in this thesis support a novel mechanism for
chemoprevention by SFN in vivo, through inhibition of histone deacetylase.
The findings also imply that SFN will offer significant protection against at
least two of the major cancer killers in the US, namely colon and prostate
cancer. / Graduation date: 2005
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/29723 |
| Date | 29 April 2005 |
| Creators | Myzak, Melinda C. |
| Contributors | Dashwood, Roderick H., Ho, Emily |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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