Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells.
Sulforaphane (SFN), an isothiocyanate first isolated from broccoli, exhibits chemopreventive properties in prostate cancer cells through mechanisms that are poorly understood. We recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells, namely the inhibition of histone deacetylase (HDAC). Here, we show that addition of 15 microM SFN also inhibited HDAC activity by 40, 30 and 40% in BPH-1, LnCaP and PC-3 prostate epithelial cells, respectively. The inhibition of HDAC was accompanied by a 50-100% increase in acetylated histones in all three prostate cell lines, and in BPH-1 cells treated with SFN there was enhanced interaction of acetylated histone H4 with the promoter region of the P21 gene and the bax gene. A corresponding 1.5- to 2-fold increase was seen for p21Cip1/Waf1 and Bax protein expression, consistent with previous studies using HDAC inhibitors, such as trichostatin A. The downstream events included cell cycle arrest and activation of apoptosis, as evidenced by changes in cell cycle kinetics and induction of multi-caspase activity. These findings provide new insight into the mechanisms of SFN action in benign prostate hyperplasia, androgen-dependent prostate cancer and androgen-independent prostate cancer cells, and they suggest a novel approach to chemoprotection and chemotherapy of prostate cancer through the inhibition of HDAC.
Myzak
Melinda C
MC
Linus Pauling Institute, Molecular and Cellular Biology Program, Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR 97331, USA.
Hardin
Karin
K
Wang
Rong
R
Dashwood
Roderick H
RH
Ho
Emily
E
D000728:Androgens / Q000502:physiology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D004847:Epithelial Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D017879:Isothiocyanates; D008297:Male; D011467:Prostate / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D011470:Prostatic Hyperplasia / Q000150:complications / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000517:prevention & control*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*
D000728:Androgens; D016588:Anticarcinogenic Agents; D056572:Histone Deacetylase Inhibitors; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D006655:Histone Deacetylases; C016766:sulforaphane