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Vorinostat differentially alters 3D nuclear structure of cancer and non-cancerous esophageal cells. Sci Rep 2016 08 09;6:30593

Date

08/10/2016

Pubmed ID

27503568

Pubmed Central ID

PMC4977554

DOI

10.1038/srep30593

Scopus ID

2-s2.0-84981290391   3 Citations

Abstract

The histone deacetylase (HDAC) inhibitor vorinostat has received significant attention in recent years as an 'epigenetic' drug used to treat solid tumors. However, its mechanisms of action are not entirely understood, particularly with regard to its interaction with the aberrations in 3D nuclear structure that accompany neoplastic progression. We investigated the impact of vorinostat on human esophageal epithelial cell lines derived from normal, metaplastic (pre-cancerous), and malignant tissue. Using a combination of novel optical computed tomography (CT)-based quantitative 3D absorption microscopy and conventional confocal fluorescence microscopy, we show that subjecting malignant cells to vorinostat preferentially alters their 3D nuclear architecture relative to non-cancerous cells. Optical CT (cell CT) imaging of fixed single cells showed that drug-treated cancer cells exhibit significant alterations in nuclear morphometry. Confocal microscopy revealed that vorinostat caused changes in the distribution of H3K9ac-marked euchromatin and H3K9me3-marked constitutive heterochromatin. Additionally, 3D immuno-FISH showed that drug-induced expression of the DNA repair gene MGMT was accompanied by spatial relocation toward the center of the nucleus in the nuclei of metaplastic but not in non-neoplastic cells. Our data suggest that vorinostat's differential modulation of 3D nuclear architecture in normal and abnormal cells could play a functional role in its anti-cancer action.

Author List

Nandakumar V, Hansen N, Glenn HL, Han JH, Helland S, Hernandez K, Senechal P, Johnson RH, Bussey KJ, Meldrum DR

Author

Roger H. Johnson PhD Associate Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Line, Tumor
Cell Nucleus
Cell Survival
Epithelial Cells
Esophageal Neoplasms
Esophagus
Histone Deacetylase Inhibitors
Histones
Humans
Hydroxamic Acids
Imaging, Three-Dimensional
Microscopy, Confocal
Microscopy, Fluorescence