title: Combination of the histone deacetylase inhibitor depsipeptide and 5-fluorouracil upregulates major histocompatibility complex class II and p21 genes and activates caspase-3/7 in human colon cancer HCT-116 cells.
abstract: Epigenetic anticancer drugs such as histone deacetylase (HDAC) inhibitors have been combined with existing anticancer drugs for synergistic or additive effects. In the present study, we found that a very low concentration of depsipeptide, an HDAC inhibitor, potentiated the antitumor activity of 5-fluorouracil (5-FU) in a human colon cancer cell model using HCT-116, HT29, and SW48 cells via the inhibition of colony formation ability or cellular viability. Exposure to a combination of 5-FU (1.75 µM) and 1 nM depsipeptide for 24 and 48 h resulted in a 3- to 4-fold increase in activated caspase-3/7, while 5-FU alone failed to activate caspase-3/7. Microarray and subsequent gene ontology analyses revealed that compared to 5-FU or depsipeptide alone, the combination treatment of 5-FU and depsipeptide upregulated genes related to cell death and the apoptotic process consistent with the inhibition of colony formation and caspase-3/7 activation. These analyses indicated marked upregulation of antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class (GO:0002504) and MHC protein complex (GO:0042611). Compared with vehicle controls, the cells treated with the combination of 5-FU and depsipeptide showed marked induction (3- to 8.5-fold) of expression of MHC class II genes, but not of MHC class I genes. Furthermore, our global analysis of gene expression, which was focused on genes involved in the molecular regulation of MHC class II genes, showed enhancement of pro-apoptotic PCAF and CIITA after the combination of 5-FU and depsipeptide. These results may indicate a closer relationship between elevation of MHC class II expression and cellular apoptosis induced by the combination of depsipeptide and 5-FU. To the best of our knowledge, this is the first study to report that the combination of 5-FU and depsipeptide induces human colon cancer cell apoptosis in a concerted manner with the induction of MHC class II gene expression.
authors: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
authors: Kouji
authors: K
authors: Okada
authors: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
authors: Shuko
authors: S
authors: Hakata
authors: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
authors: Jun
authors: J
authors: Terashima
authors: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
authors: Toshie
authors: T
authors: Gamou
authors: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
authors: Wataru
authors: W
authors: Habano
authors: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
authors: Shogo
authors: S
authors: Ozawa
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D047630:Depsipeptides / Q000008:administration & dosage*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D000949:Histocompatibility Antigens Class II; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D005472:Fluorouracil