Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice - PubMed (original) (raw)

Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice

Melinda C Myzak et al. FASEB J. 2006 Mar.

Abstract

Sulforaphane (SFN) is an isothiocyanate from broccoli that induces phase 2 detoxification enzymes. We recently reported that SFN acts as a histone deacetylase (HDAC) inhibitor in human colon cancer cells in vitro, and the present study sought to extend these findings in vivo. In mice treated with a single oral dose of 10 mumol SFN, there was significant inhibition of HDAC activity in the colonic mucosa after 6 h, and immunoblots revealed a concomitant increase in acetylated histones H3 and H4, which returned to control levels by 48 h. Longer-term treatment with SFN in the diet resulted in levels of acetylated histones and p21(WAF1) in the ileum, colon, prostate, and peripheral blood mononuclear cells that were elevated compared with controls. Consistent with these findings, SFN suppressed tumor development in Apc(min) mice, and there was an increase in acetylated histones in the polyps, including acetylated histones specifically associated with the promoter region of the P21 and bax genes. These results provide the first evidence for HDAC inhibition by SFN in vivo and imply that such a mechanism might contribute to the cancer chemoprotective and therapeutic effects of SFN, alone or in combination with other HDAC inhibitors currently undergoing clinical trials.

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Figures

Figure 1

Figure 1

SFN and SFN-NAC inhibit HDAC activity and induce accumulation of acetylated histones in mouse colonic mucosa. Mice were treated by gavage with 10 μmol SFN, 10 μmol SFN-NAC, or vehicle alone, and colonic mucosa was isolated after 6 h. A) HDAC activities, expressed as mean ± SE, n = 3; ***P < 0.001. B) Colonic mucosa from each mouse was analyzed by immunoblot for acetylated histone H3 and acetylated histone H4; β-actin was used as a loading control.

Figure 2

Figure 2

Dietary SFN suppresses polyp formation in _Apc_min mice. Mice consumed ~6 μmol SFN/day for 10 wk in the diet or AIN93G diet alone (controls). A) Suppression of overall tumor multiplicity; B) Suppression according to tumor distribution in the GI tract. Mean ± SE, n = 15; *P < 0.05; **P < 0.01.

Figure 3

Figure 3

Summary of key findings. In the _Apc_min mouse, HDAC/co-repressor complexes maintain a tightly restricted chromatin configuration, which limits access of transcription factors to DNA, and represses genes required for cell cycle checkpoint control and apoptosis. Inhibition of HDAC by SFN enables acetyl groups (“ac”) to be added to histone tails, loosening DNA/chromatin interactions, and allowing access of transcription factors to the promoters of genes such as P21 and bax. Re-expression of these genes triggers cell cycle arrest and apoptosis in transformed cells and microadenomas, thereby suppressing polyp formation.

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