Histone deacetylase inhibitors selectively suppress expression of HDAC7.
There are 18 histone deacetylases (HDAC) generally divided into four classes based on homology to yeast HDACs. HDACs have many protein substrates in addition to histones that are involved in regulation of gene expression, cell proliferation, and cell death. Inhibition of HDACs can cause accumulation of acetylated forms of these proteins, thus altering their function. HDAC inhibitors (HDACi), such as the hydroxamic acid-based vorinostat (suberoylanilide hydroxamic acid), inhibit the zinc-containing classes I, II, and IV, but not the NAD(+)-dependent class III, enzymes. HDACis are a group of novel anticancer agents. Vorinostat is the first HDACi approved for clinical use in the treatment of the cancer cutaneous T-cell lymphoma. Factors affecting expression of HDACs are not well understood. This study focuses on the effect of the HDACi vorinostat on the expression of class I and class II HDACs. We found that vorinostat selectively down-regulates HDAC7 with little or no effect on the expression of other class I or class II HDACs. Fourteen cell lines were examined, including normal, immortalized, genetically transformed, and human cancer-derived cell lines. Down-regulation of HDAC7 by vorinostat is more pronounced in transformed cells sensitive to inhibitor-induced cell death than in normal cells or cancer cells resistant to induced cell death. Modulation of HDAC7 levels by small interfering RNA-mediated knockdown or by HDAC7 overexpression is associated with growth arrest but without detectable changes in acetylation of histones or p21 gene expression. Selective down-regulation of HDAC7 protein may serve as a marker of response of tumors to HDACi.
Dokmanovic
Milos
M
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Perez
Gisela
G
Xu
Weisheng
W
Ngo
Lang
L
Clarke
Cathy
C
Parmigiani
Raphael B
RB
Marks
Paul A
PA
D000107:Acetylation; D015152:Blotting, Northern; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011467:Prostate / Q000187:drug effects / Q000201:enzymology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D000077337:Vorinostat
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D000077337:Vorinostat; C543273:HDAC7 protein, human; D006655:Histone Deacetylases