Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice.
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.
Myzak
Melinda C
MC
Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331-6512, USA.
Dashwood
W Mohaiza
WM
Orner
Gayle A
GA
Ho
Emily
E
Dashwood
Roderick H
RH
D000107:Acetylation / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002843:Chromatin / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D017491:Genes, APC; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000517:prevention & control*; D007417:Intestinal Polyps / Q000235:genetics / Q000517:prevention & control; D017879:Isothiocyanates; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016037:Single-Blind Method; D013454:Sulfoxides; D013861:Thiocyanates / Q000008:administration & dosage / Q000494:pharmacology*
D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; C016766:sulforaphane