title: Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth: implications for therapy.
abstract: There is an urgent need to develop new strategies to treat ovarian cancer, the most deadly gynecologic malignancy. Histone deacetylase (HDAC) inhibitors are emerging as novel therapeutic drugs in the treatment of a variety of cancers, including those resistant to standard chemotherapy. Since there are multiple HDAC isoforms, determining the precise role of individual HDAC isoenzymes in the growth and progression of ovarian cancer has the potential to influence the use of selective HDAC inhibitors as strategic therapeutic agents that elicit fewer undesirable side effects. Unfortunately, there is limited information about the expression of HDAC isoforms in human ovarian tissues. This report provides evidence for the first time that Class I HDACs are expressed at significantly higher levels in ovarian cancers in comparison to normal ovarian tissues, with no significant difference in Class II HDAC expression between the two groups. Furthermore, ovarian cancer cells are far more sensitive than normal ovarian cells to the potent HDAC inhibitor romidepsin (FK228), a drug that displays greater inhibitory selectivity for Class I HDACs over Class II isoforms. Using small interfering RNA (siRNA) methodology, we demonstrate that knocking down the gene expression of HDAC3 and other members of the Class I HDAC family suppresses ovarian cancer cell growth. Taken together, the present studies offer several novel findings that have direct relevance for the strategic use of inhibitors that target Class I HDACs, particularly HDAC3, in the treatment of ovarian cancer.
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Meharry Medical College, Nashville, Tennessee 37208, USA.
authors: Dineo
authors: D
authors: Khabele
authors: Deok-Soo
authors: DS
authors: Son
authors: Angelika K
authors: AK
authors: Parl
authors: Gary L
authors: GL
authors: Goldberg
authors: Leonard H
authors: LH
authors: Augenlicht
authors: John M
authors: JM
authors: Mariadason
authors: Valerie Montgomery
authors: VM
authors: Rice
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D047630:Depsipeptides / Q000494:pharmacology*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing / Q000187:drug effects*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D000077337:Vorinostat
chemical_list: D000903:Antibiotics, Antineoplastic; D002087:Butyrates; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D000077337:Vorinostat; C087123:romidepsin; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases