Abstract
Site-specific histone modifications are important epigenetic regulators of gene expression. As deregulation of genes often results in complex disorders, corrective modulation of site-specific histone marks could be a powerful therapeutic or disease-preventive strategy. However, such modulation by dietary compounds and the resulting impact on disease risk remain relatively unexplored. Here we examined phenethylisothiocyanate (PEITC), a common dietary compound derived from cruciferous vegetables with known chemopreventive properties under experimental conditions, as a possible modulator of histone modifications in human colon cancer cells. The present study reports novel, dynamic, site-specific chemical changes to histone H3 in a gene-promoter-specific manner, associated with PEITC exposure in human colon tumor-derived SW480 epithelial cells. In addition, PEITC attenuated cell proliferation in a concentration- and time-dependent manner, likely mediated by caspase-dependent apoptotic signalling. The effects of PEITC on histone modifications and gene expression changes were achieved at low, non-cytotoxic concentrations, in contrast to the higher concentrations necessary to halt cancer cell proliferation. Increased understanding of specific epigenetic alterations by dietary compounds may provide improved chemopreventive strategies for reducing the healthcare burden of cancer and other human diseases.
Highlights
Cancer remains the second-leading cause of all deaths in the United States [1]
The alterations of site-specific chromatin modifications, known as epigenetic changes, are relevant to clinical oncology, as they are closely associated with gene expression and network perturbations in the diseased state [6,7]
Antibodies used for the chromatin immunoprecipitation (ChIP) assay were anti-acetyl-Histone H3, anti-trimethylHistone H3 (Lys27), and rabbit IgG for negative control samples from Upstate Biotechnology (Billerica, MA) and anti-dimethylHistone H3 (Lys9) from Abcam (Cambridge, MA)
Summary
Cancer remains the second-leading cause of all deaths in the United States [1]. many dietary compounds can potently modulate various molecular targets, leading to prevention of cancer initiation, promotion, and progression. We investigated H3acetylation (H3-Ac) and site-specific H3 lysine methylations (H3K27me and H3K9me2) in association with phenethylisothiocyanate (PEITC)-mediated gene expression modulation in human colon cancer cells This is a follow up of our previous reports on PEITC as a dietary compound with potential anti-inflammatory functions in various experimental models [12,13]. Key players in this association include transcription factors, such as nuclear factor kappa B (NFkB) and signal transducers and activators of transcription (STATs), cytokines/chemokines, and matrix metalloproteinases (MMPs), a multigene family of zinc-dependent extracellular matrix-remodeling endopeptidases These cellular mediators, some of which we studied previously in mouse models [12,13], have important functions related to the bypassing of adaptive immunity, proliferation, survival of malignant cells, tumor growth, angiogenesis, invasion, and metastasis [17,18,19,20]. The current study investigated chromatin changes in association with PEITCmediated modulation of the expression of these mediators in human colon cancer cells
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