Evidence for the role of promoter methylation in the regulation of MMP-9 gene expression

Chicoine, Éric; Estève, Pierre‐Olivier; Robledo, Olivier; Themsche, Céline Van; Potworowski, Édouard F.; St‐Pierre, Yves

doi:10.1016/s0006-291x(02)02283-0

Cited by 86 publications

(69 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our target site, the K36 bp site, is seated in the second concentration zone of ciselements, which includes AP-1, KER M9 and Sp-1 binding sites. In a previous study, the Sp-1 site has been demonstrated to be critical for MMP9 transcription and heavily hypomethylated in murine lymphoma cells that overexpress MMP9 (Chicoine 2002). The results from Roach et al (2005) and our current study further confirm the key role of Sp-1 as a regulator of the human MMP9 promoter.…”

Section: Discussionsupporting

confidence: 86%

“…However, in our experiment, no significant findings were observed at the two sites closest to the NF-kB binding element (K624 and K562 bp). The synergistic cooperation of AP-1 with either NF-kB or Sp-1 was previously shown to be required for transcription of the MMP9 gene (Chicoine 2002). Therefore, we presume that Sp-1, instead of NF-kB, is more important the in regulation process that was observed in our study.…”

Section: Discussionsupporting

confidence: 60%

“…In particular, site-specific demethylation was reported to function in the dynamic regulation of genes that require rapid responses to specific stimuli (Wu & Zhang 2010). Chicoine (2002) indicated, for the first time, that changes in the status of DNA methylation could affect the transcriptional activity of the MMP9 promoter in murine thymic lymphoma cell lines. Roach et al (2005) demonstrated that perturbed synthesis of MMP9 in osteoarthritic chondrocytes had resulted from demethylation at one particular CpG site in the MMP9 promoter.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of site-specific DNA demethylation in TNFα-induced MMP9 expression in keratinocytes

Li¹,

Ren²,

Yang³

et al. 2013

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Inappropriately high expression of matrix metalloproteinase 9 (MMP9) in the late stage of diabetic foot ulcers suppresses wound healing. The underlying mechanisms are not completely understood. Site-specific demethylation was reported to function in the regulation of genes, causing persistent high expression of target genes. Therefore, this study was designed to determine whether site-specific DNA demethylation was a key regulatory component of MMP9 expression in diabetic wound healing, and to further verify the crucial CpG site(s). Human keratinocyte cell line (HaCaT) cells were exposed to tumor necrosis factor a (TNFa), and changes in MMP9 expression and DNA methylation status were detected. We found TNFa treatment increased endogenous MMP9 expression in HaCaT cells and decreased the DNA methylation percentage at the K36 bp promoter site in a timedependent manner. Bisulfite sequencing PCR revealed differentially demethylated CpG sites in the human MMP9 promoter region, but only the change at the K36 bp site was statistically significant. Dual-luciferase reporter assays showed that the promoter with only the K36 bp site demethylated had slightly higher transcriptional activity than the promoter with all other sites except the K36 bp site demethylated. Our results demonstrate that site-specific DNA demethylation plays an important role in MMP9 expression in TNFa-stimulated keratinocytes. The K36 bp site in the MMP9 gene promoter is crucial to this effect, but other CpG sites may exert synergistic effects. Collectively, these data may contribute to the future development of novel therapeutic strategies to treat diabetic foot ulcers and prevent gangrene and amputation. Key Words" keratinocytes " tumor necrosis factor a " matrix metalloproteinase 9" site-specific DNA demethylation " diabetic foot ulcers

show abstract

Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of site-specific DNA demethylation in TNFα-induced MMP9 expression in keratinocytes

Li¹,

Ren²,

Yang³

et al. 2013

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…It is still unclear how pro-migratory genes, including MMPs, tissue inhibitors of metalloproteinases (TIMPs), ECM proteins, and cell adhesion and signaling receptors, are controlled epigenetically (21)(22)(23)(24)(25). Genome-wide transcriptional profiling alone (26 -28) estimates the levels of the individual mRNAs in the cell sample, but it does not determine the transcriptional state of the individual genes.…”

mentioning

confidence: 99%

Microarray-based Transcriptional and Epigenetic Profiling of Matrix Metalloproteinases, Collagens, and Related Genes in Cancer

Chernov

Baranovskaya

Golubkov

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

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.Cell locomotion is a well orchestrated, multi-component, molecular and cellular process that involves multiple and complex regulatory pathways. Proteolysis and proteinases including MMPs, 2 a family of 24 individual enzymes in humans, play an important role in cell function and especially in the processes of cell migration and invasion (1-3). In addition to MMPs, multiple genes and respective cellular proteins, including extracellular matrix (ECM) proteins, integrins, and other adhesion signaling receptors, are also directly involved in cell locomotion. 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). In malignancies, DNA methylation is frequently dysregulated. By interfering with the transcription initiation, methylation of the CpG islands (CpGi) inhibits transcription and represses tumor suppressor genes. Acetylation of the core histones H3, H4, H2A, and H2B is normally associated with the activation of gene transcription (7). Acetyl groups are added by a family of histone acetyltransferases and are removed by histone deacetylases. In turn, methylation of the lysine residues in the histone tails may lead to either transcriptional activation or ...

show abstract

“…In several tumor types, the expression of a large repertoire of tumor suppressor genes has been found to be reduced by DNA methylation (Ballestar and Esteller, 2008;Baylin and Jones, 2007;Graff et al, 1997;Robertson, 2005). Tumor suppressor genes are among the pivotal genes known to be regulated by CpG methylation (Ballestar and Esteller, 2008;Chicoine et al, 2002;Murayama et al, 2006;Na et al, 2010;Park et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Up-Regulation of Leukemia Inhibitory Factor (LIF) Gene During the Progression to Breast Cancer

Shin

Park

Jang

2011

Molecules and Cells

View full text Add to dashboard Cite

The interleukin 6 family of cytokines including leukemia inhibitory factor (LIF) regulates the progression of several types of cancer. However, although LIF overexpression during breast cancer progression was observed in our previous report, the molecular mechanisms responsible for this deregulation remain largely unknown. Here we show that LIF expression is epigenetically up-regulated via DNA demethylation and changes in histone methylation status within its promoter region in the isogenic MCF10 model. Bisulfite sequencing revealed the CpG pairs within the promoter region are hypermethylated in normal breast epithelial cells, but extensively demethylated as breast cancer progresses. In agreement with the DNA methylation pattern, our chromatin immunoprecipitation showed that inactive epigenetic marks such as MeCP2 occupancy and histone H3-Lys9-dimethylation significantly decreased during the progression to breast cancer but an active histone mark was increased in an inverse manner. Also, the occupancy of the transcription factor Sp1, which has higher affinity for hypomethylated CpGs, increased. RNAimediated knockdown of LIF expression resulted in a significant reduction of cell growth and colony formation in breast cancer cells, suggesting the potential role of LIF-LIF receptor axis in autocrine stimulation of cancer cells. Collectively, our data suggest that the epigenetic up-regulation of the LIF gene likely play an important role in the development of breast cancer.

show abstract

Evidence for the role of promoter methylation in the regulation of MMP-9 gene expression

Cited by 86 publications

References 33 publications

Role of site-specific DNA demethylation in TNFα-induced MMP9 expression in keratinocytes

Role of site-specific DNA demethylation in TNFα-induced MMP9 expression in keratinocytes

Microarray-based Transcriptional and Epigenetic Profiling of Matrix Metalloproteinases, Collagens, and Related Genes in Cancer

Epigenetic Up-Regulation of Leukemia Inhibitory Factor (LIF) Gene During the Progression to Breast Cancer

Contact Info

Product

Resources

About