Abstract
The onset and progression of breast cancer are linked to genetic and epigenetic changes that alter the normal programming of cells. Epigenetic modifications of DNA and histones contribute to chromatin structure that result in the activation or repression of gene expression. Several epigenetic pathways have been shown to be highly deregulated in cancer cells. Targeting specific histone modifications represents a viable strategy to prevent oncogenic transformation, tumor growth or metastasis. Methylation of histone H3 lysine 4 has been extensively studied and shown to mark genes for expression; however this residue can also be acetylated and the specific function of this alteration is less well known. To define the relative roles of histone H3 methylation (H3K4me3) and acetylation (H3K4ac) in breast cancer, we determined genomic regions enriched for both marks in normal-like (MCF10A), transformed (MCF7) and metastatic (MDA-MB-231) cells using a genome-wide ChIP-Seq approach. Our data revealed a genome-wide gain of H3K4ac associated with both early and late breast cancer cell phenotypes, while gain of H3K4me3 was predominantly associated with late stage cancer cells. Enrichment of H3K4ac was over-represented at promoters of genes associated with cancer-related phenotypic traits, such as estrogen response and epithelial-to-mesenchymal transition pathways. Our findings highlight an important role for H3K4ac in predicting epigenetic changes associated with early stages of transformation. In addition, our data provide a valuable resource for understanding epigenetic signatures that correlate with known breast cancer-associated oncogenic pathways.
Highlights
Epigenetic changes in chromatin structure and posttranslational modification in response to developmental, environmental and hormonal stimuli, mediate changes in transcriptional output that define distinct cell phenotypes
We focused on histone modifications associated with H3K4, a lysine residue associated with regulation of gene transcription, to evaluate the histone modifications associated with biological responses of epithelial and cancer cells
We observed a global increase in acetylated H3K4 promoters in both cancer cell lines (MCF7, MDA-MB-231), and a global increase in H3K4 tri- methylated promoters in the MDA-MB-231 metastatic cell line; these findings suggest that oncogenic progression is associated with increases in both of these marks
Summary
Epigenetic changes in chromatin structure and posttranslational modification in response to developmental, environmental and hormonal stimuli, mediate changes in transcriptional output that define distinct cell phenotypes. A major component of epigenetic regulation is the post-translational modification of histone tails that affects chromatin structure by destabilizing histone interactions with DNA, altering nucleosome contacts, and forming binding sites for transcriptional regulators that influences gene expression. Under normal circumstances these shifts in histone modifications result in programmed phenotypic changes such as cell differentiation. The role of acetylation of H3K4 has been less studied This is surprising given the importance of other acetylation marks, and given the implication of histone acetyltransferase and deacetylase enzymes in the progression of several types of tumors [7, 8]. We tested the hypothesis that the differential enrichment of these specific histone marks may define the cellular and molecular characteristics that are hallmarks of breast cancer cell phenotypes
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