A novel mechanism of chemoprevention by sulforaphane: Inhibition of histone deacetylase.

摘要

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 Apcmin 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.