RT Journal Article
SR Electronic
T1 Identification of Novel Isoform-Selective Inhibitors within Class I Histone Deacetylases
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 720
OP 728
DO 10.1124/jpet.103.055541
VO 307
IS 2
A1 Hu, Erding
A1 Dul, Edward
A1 Sung, Chiu-Mei
A1 Chen, Zunxuan
A1 Kirkpatrick, Robert
A1 Zhang, Gui-Feng
A1 Johanson, Kyung
A1 Liu, Ronggang
A1 Lago, Amparo
A1 Hofmann, Glenn
A1 Macarron, Ricardo
A1 De Los Frailes, Maite
A1 Perez, Paloma
A1 Krawiec, John
A1 Winkler, James
A1 Jaye, Michael
YR 2003
UL http://jpet.aspetjournals.org/content/307/2/720.abstract
AB Histone deacetylases (HDACs) represent an expanding family of protein modifying-enzymes that play important roles in cell proliferation, chromosome remodeling, and gene transcription. We have previously shown that recombinant human HDAC8 can be expressed in bacteria and retain its catalytic activity. To further explore the catalytic activity of HDACs, we expressed two additional human class I HDACs, HDAC1 and HDAC3, in baculovirus. Recombinant HDAC1 and HDAC3 fusion proteins remained soluble and catalytically active and were purified to near homogeneity. Interestingly, trichostatin (TSA) was found to be a potent inhibitor for all three HDACs (IC50 value of ∼0.1-0.3 μM), whereas another HDAC inhibitor MS-27-275 (N-(2-aminophenyl)-4-[N-(pyridin-3-methyloxycarbonyl)-aminomethyl]benzamide) preferentially inhibited HDAC1 (IC50 value of ∼0.3 μM) versus HDAC3 (IC50 value of ∼8 μM) and had no inhibitory activity toward HDAC8 (IC50 value >100 μM). MS-27-275 as well as TSA increased histone H4 acetylation, induced apoptosis in the human colon cancer cell line SW620, and activated the simian virus 40 early promoter. HDAC1 protein was more abundantly expressed in SW620 cells compared with that of HDAC3 and HDAC8. Using purified recombinant HDAC proteins, we identified several novel HDAC inhibitors that preferentially inhibit HDAC1 or HDAC8. These inhibitors displayed distinct properties in inducing histone acetylation and reporter gene expression. These results suggest selective HDAC inhibitors could be identified using recombinantly expressed HDACs and that HDAC1 may be a promising therapeutic target for designing HDAC inhibitors for proliferative diseases such as cancer. The American Society for Pharmacology and Experimental Therapeutics