Abstract
Epigenetic parameters (DNA methylation, histone modifications, and miRNAs) play a significant role in cancer. To identify the common epigenetic signatures of both the individual matrix metalloproteinases (MMPs) and the additional genes, the function of which is also linked to proteolysis, migration, and tumorigenesis, we performed epigenetic profiling of 486 selected genes in unrelated non-migratory MCF-7 breast carcinoma and highly migratory U251 glioma cells. Genome-wide transcriptional profiling, quantitative reverse transcription-PCR, and microRNA analyses were used to support the results of our epigenetic studies. Transcriptional silencing in both glioma and breast carcinoma cells predominantly involved the repressive histone H3 Lys-27 trimethylation (H3K27me3) mark. In turn, epigenetic stimulation was primarily performed through a gain in the histone H3 Lys-4 dimethylation (H3K4me2) and H3 hyperacetylation and by a global reduction of H3K27me3. Inactive pro-invasive genes in MCF-7 cells but not in U251 cells frequently exhibited a stem cell-like bivalent mark (enrichment in both H3K27me3 and H3K4me2), a characteristic of developmental genes. In contrast with other MMPs, MMP-8 was epigenetically silenced in both cell types, thus providing evidence for the strict epigenetic control of this anti-tumorigenic proteinase in cancer. Epigenetic stimulation of multiple collagen genes observed in cultured glioma cells was then directly confirmed using orthotopic xenografts and tumor specimens. We suggest that the epigenetic mechanisms allow gliomas to deposit an invasion-promoting collagen-enriched matrix and then to use this matrix to accomplish their rapid migration through the brain tissue.
Highlights
JUNE 18, 2010 VOLUME 285 NUMBER 25 important role in cell function and especially in the processes of cell migration and invasion [1,2,3]
Gene products involved in cell locomotion, angiogenesis, tumor progression, and survival are all potential targets of epigenetic regulation via DNA methylation and histone modifications [4] and by micro-RNA mechanisms [5, 6]
Methylation of the H3K9, H3K27, and H4K20 lysine residues promotes the interaction of the modified histones with the heterochromatin protein 1 (HP1) or its homologues, and these events lead to gene silencing [12,13,14,15]
Summary
JUNE 18, 2010 VOLUME 285 NUMBER 25 important role in cell function and especially in the processes of cell migration and invasion [1,2,3]. Gene products involved in cell locomotion, angiogenesis, tumor progression, and survival are all potential targets of epigenetic regulation via DNA methylation and histone modifications [4] and by micro-RNA (miRNA) mechanisms [5, 6]. Methylation of the lysine residues in the histone tails may lead to either transcriptional activation or repression. In stem cells and in T cells, H3K4 and H3K27 methylation frequently occurs in histones that are associated with the temporarily silenced developmental genes, the rapid activation of which is initiated by developmental stimuli (16 –18). MiRNAs, which potentially can regulate ϳ30% of human genes [20], are deregulated in cancers by different mechanisms, including epigenetic activation/repression [5, 6] Epigenetic Profiling of MMPs and Collagens in Cancer [19]. miRNAs, which potentially can regulate ϳ30% of human genes [20], are deregulated in cancers by different mechanisms, including epigenetic activation/repression [5, 6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
