Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

Pulukuri, Sai Murali Krishna; Patibandla, Sruthi; Patel, Jitendra; Estes, Norman C.; Rao, Jasti S.

doi:10.1038/sj.onc.1210329

Cited by 89 publications

(74 citation statements)

References 20 publications

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“…According to different studies, TIMP-2 expression was found to be both upregulated and downregulated in various cancers (DeClerck et al, 1992;Imren et al, 1996;Gomez et al, 1997;Valente et al, 1998;Pulukuri et al, 2007). Recent data identified the downregulation of TIMP-2 expression by epigenetic mechanisms (Suzuki et al, 2002;Ivanova et al, 2004;Galm et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

S-adenosylmethionine, a methyl donor, up regulates tissue inhibitor of metalloproteinase-2 in colorectal cancer

Hussain

Khan²,

Shahid³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. DNA methylation is a fundamental epigenetic mechanism in regulating the expression of genes controlling crucial cell functions in cancer development. Gene silencing via CpG island methylation/ demethylation in the promoter region is one of the mechanisms by which different genes are inactivated/activated in human cancers. Tissue inhibitor of metalloproteinase-2 (TIMP-2) is known to antagonize matrix metalloproteinase (MMP) activity and to suppress tumor growth, angiogenesis, invasion, and metastasis. TIMP-2 expression has been found to be both upregulated and downregulated in various cancers. The inconsistent TIMP-2 expression and unclear epigenetic regulation lead us to investigate its role in colorectal cancer in the presence of a methylating Hypomethylation status of tissue inhibitor of metalloproteinase agent. Highly invasive human colorectal cells SW-620 were treated with the methyl donor S-adenosylmethionine (SAM) and its effect was evaluated by cell proliferation, cell cycle, invasion and migration assay. The ability of SAM to down regulate a panel of activated prometastatic, angiogenesis and growth-and cell cycle-regulatory genes was evaluated using end-point and real-time PCR. Treatment of SW-620 with SAM diminished cell proliferation and altered cell cycle kinetic G 2 /M phase cell cycle arrest. An in vitro matrigel invasion assay of SAM-treated cells showed a significant reduction in the invasive potential compared to untreated SW-620 cells. Treatment of SW-620 cells with SAM resulted in activation of TIMP-2 and inhibition of the expression of genes such as MMP (MMP-2, MT1-MMP), urokinase plasminogen activator, and vascular endothelial growth factors. The level of expression of tumor suppressor and apoptotic genes was not significantly higher compared to the untreated control. No changes in the levels of expression of genes (growth and cell cycle regulator), such as TGF-β, Smad2, Smad4, and p21 were observed. Our data support the hypothesis that TIMP-2, along with other prometastatic genes, is hypomethylated and expressed differently in colorectal cancer. Further in-depth analysis is warranted to confirm the promoter region CpG methylation pattern of the TIMP-2 gene.

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Section: Discussionmentioning

confidence: 99%

S-adenosylmethionine, a methyl donor, up regulates tissue inhibitor of metalloproteinase-2 in colorectal cancer

Hussain

Khan²,

Shahid³

et al. 2013

Genet. Mol. Res.

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“…In this connection, both in silico prediction and luciferase assay have identified MeCP2 as the direct target of miR-212, an miRNA frequently downregulated in gastric cancer (Wada et al, 2009). Increased expression of MeCP2 is associated with enhanced epigenetic silencing of various important tumor suppressors, such as STAT5A (Zhang et al, 2007b), TIMP-2 (Pulukuri et al, 2007) and C/EBPa/d (Tada et al, 2006;Agrawal et al, 2007) in other types of cancer. Moreover, downregulation of MeCP2 induces senescence in mesenchymal stem cells (Squillaro et al, 2010), whereas its expression is required for prostate cancer cell proliferation (Bernard et al, 2006).…”

Section: Dysregulated Mirnas In Gastric Cancermentioning

confidence: 99%

MicroRNA dysregulation in gastric cancer: a new player enters the game

et al. 2010

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“…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.…”

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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

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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 ...

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Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

Cited by 89 publications

References 20 publications

S-adenosylmethionine, a methyl donor, up regulates tissue inhibitor of metalloproteinase-2 in colorectal cancer

S-adenosylmethionine, a methyl donor, up regulates tissue inhibitor of metalloproteinase-2 in colorectal cancer

MicroRNA dysregulation in gastric cancer: a new player enters the game

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

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