title: Cell cycle blockade and differentiation of ovarian cancer cells by the histone deacetylase inhibitor trichostatin A are associated with changes in p21, Rb, and Id proteins.
abstract: Inhibitors of histone deacetylase activity are emerging as a potentially important new class of anticancer agents. In the current studies, exposing A2780 ovarian cancer cells to the histone deacetylase inhibitor trichostatin A (TSA) produced a marked change in cellular morphology, proliferation, and differentiation. Within 24 h of TSA treatment, there was a morphological transformation of the cells, with increased cytoplasm, a more epithelial-like columnar appearance, and the emergence of distinct cellular boundaries. Commensurate with the morphological transformation, TSA also inhibited cell proliferation; cells treated with TSA for 72 h increased to 110% of the initial cell numbers versus control cell numbers of 622%, with a corresponding reduction in mitotic activity and a flow cytometry S-phase fraction of 3.9% in TSA-treated cells versus 28.8% for control. TSA also induced epithelial-like differentiation with increased cytokeratin expression from 2% of controls to 22-25% of TSA-treated cells and the reappearance of intercellular plasma membrane junctions and primitive microvilli. Immunocytochemical analyses indicate the molecular mechanism underlying the actions of TSA on A2780 cell cycle progression and differentiation involves reexpression of the CDK inhibitor p21. Elevated levels of p21, in TSA-treated cells, were associated with a reduction in the phosphorylation of the cell cycle regulator retinoblastoma protein (Rb). TSA also caused a decrease in the helix-loop-helix inhibitor of differentiation/DNA binding protein Id1, with no change in Id2 levels. In conclusion, the observed TSA-induced changes in p21, Rb, and Id1 are consistent with cell cycle senescence and differentiation of A2780 ovarian cancer cells.
authors.affiliation: Department of Medicine, Cancer Research Laboratory, LDS Hospital, Salt Lake City, Utah 84143, USA. ldkstrai@ihc.com
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strait
authors.forename: Bashar
authors.initials: B
authors.lastname: Dabbas
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Hammond
authors.forename: C Terry
authors.initials: CT
authors.lastname: Warnick
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Iistrup
authors.forename: Clyde D
authors.initials: CD
authors.lastname: Ford
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D018257:Helix-Loop-Helix Motifs; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D007633:Keratins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C497453:ID1 protein, human; C497450:ID2 protein, human; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D009124:Muscle Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C058992:Tagln protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D007633:Keratins