TitleSulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice.
Publication TypeJournal Article
Year of Publication2006
AuthorsMyzak MC, W Dashwood M, Orner GA, Ho E, Dashwood RH
JournalFASEB J
Volume20
Issue3
Pagination506-8
Date Published2006 Mar
ISSN1530-6860
KeywordsAcetylation, Administration, Oral, Animals, Cell Transformation, Neoplastic, Chromatin, Drug Screening Assays, Antitumor, Genes, APC, Histone Deacetylase Inhibitors, Histones, Intestinal Mucosa, Intestinal Neoplasms, Intestinal Polyps, Isothiocyanates, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Processing, Post-Translational, Single-Blind Method, Thiocyanates
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.

DOI10.1096/fj.05-4785fje
Alternate JournalFASEB J.
PubMed ID16407454
PubMed Central IDPMC2373266
Grant ListP01 CA090890 / CA / NCI NIH HHS / United States
P01 CA090890-01A20003 / CA / NCI NIH HHS / United States
P30 ES00210 / ES / NIEHS NIH HHS / United States
CA-65525 / CA / NCI NIH HHS / United States
R01 CA080176 / CA / NCI NIH HHS / United States
CA-107693 / CA / NCI NIH HHS / United States
P01 CA090890-05S1 / CA / NCI NIH HHS / United States
CA-100608 / CA / NCI NIH HHS / United States
CA-80176 / CA / NCI NIH HHS / United States
P01 CA090890-05 / CA / NCI NIH HHS / United States
R01 CA065525 / CA / NCI NIH HHS / United States
R01 CA065525-08 / CA / NCI NIH HHS / United States
R01 CA065525-09 / CA / NCI NIH HHS / United States
R01 CA080176-05 / CA / NCI NIH HHS / United States
CA-90890 / CA / NCI NIH HHS / United States
R01 CA080176-04 / CA / NCI NIH HHS / United States
P01 CA090890-01A29001 / CA / NCI NIH HHS / United States