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

Okada,Kouji; Hakata,Shuko; Terashima,Jun; Gamou,Toshie; Habano,Wataru; Ozawa,Shogo

doi:10.3892/or.2016.5008

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

Authors:
- Kouji Okada
- Shuko Hakata
- Jun Terashima
- Toshie Gamou
- Wataru Habano
- Shogo Ozawa
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Affiliations: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan
Published online on: August 8, 2016 https://doi.org/10.3892/or.2016.5008
Pages: 1875-1885
Copyright: © Okada et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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