Marker genes to predict sensitivity to FK228, a histone deacetylase inhibitor

In this study, we detected genes sensitive to an histone deacetylase inhibitor, FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo-[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone; FR901228, depsipeptide] in vitro and identified marker genes to predict sensitivity to FK228 in vivo using Affymetrix GeneChip. Three percent of genes (205/7070) were sensitive to FK228 in vitro, 105 and 100 genes, were up- and down-regulated, respectively, by FK228. Commonly up-regulated genes included p21WAF1/Cip1, interleukin-8 (IL-8), histone family, JunB, caspase 9, mitogen-activated protein kinase phosphatase 1 (MKP-1) and mitogen-activated protein kinase (MAPK) family, and commonly down-regulated genes included cyclin A and MAPK family. One percent of genes (76/7070) showed native differences in patterns of expression, when FK228-sensitive (PC-3 prostate and SC-6-JCK (SC-6) stomach) and FK228-resistant (ACHN and A-498 renal) tumors implanted in BALB/c nu/nu mice were compared. Twenty-seven and forty nine of those genes were expressed at high or low levels, respectively, in FK228-sensitive tumors. Caspase 9 and MKP-1 genes showed distinct differences in patterns of expression between FK228-sensitive and resistant tumors and have been known to have roles in apoptosis and chromatin remodeling. The expression of caspase 9 gene was higher in FK228-sensitive tumors and the expression of MKP-1 gene was higher in FK228-resistant tumors. Caspase 9 and MKP-1 genes in the other FK228-sensitive tumors had the same patterns of expression as they did in PC-3 and SC-6 tumors. Our results present profiles of gene expression related to FK228 and marker genes to predict sensitivity to FK228, such as caspase 9 and MKP-1 genes.