Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular metastasis is the most detrimental step in carcinoma disease progression, yet the mechanisms that regulate this process are poorly understood. CXCL12 and its receptor CXCR4 are co-expressed in several tissues and cell types throughout the body and play essential roles in development. Disruption of either gene causes embryonic lethality due to similar defects. Post-natally, CXCL12 signaling has a wide range of effects on CXCR4-expressing cells, including the directed migration of leukocytes, lymphocytes and hematopoietic stem cells. Recently, this signaling axis has also been described as an important regulator of directed carcinoma cell metastasis. We show herein that while CXCR4 expression remains consistent, constitutive colonic epithelial expression of CXCL12 is silenced by DNA hypermethylation in primary colorectal carcinomas as well as colorectal carcinoma-derived cell lines. Inhibition of DNA methyltransferase (Dnmt) enzymes with 5-aza-2'-deoxycytidine or genetic ablation of both Dnmt1 and Dnmt3b prevented promoter methylation and restored CXCL12 expression. Re-expression of functional, endogenous CXCL12 in colorectal carcinoma cells dramatically reduced metastatic tumor formation in mice, as well as foci formation in soft agar. Decreased metastasis was correlated with increased caspase activity in cells re-expressing CXCL12. These data constitute the unique observation that silencing CXCL12 within colonic carcinoma cells greatly enhances their metastatic potential.
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PMID:Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. 1656 88

Increased risk for the development of endometrial cancer has been associated with unopposed oestrogen exposure, hyperoestrogenic factors, and a history of breast cancer treated long-term with tamoxifen (Tam). Stromal cell-derived factor-1, currently named as CXCL12, is a chemokine that, via binding to CXCR4 receptor, activates several downstream effectors and signalling pathways responsible for proliferation, survival, and migration of cancer cells. We observed that 17beta-estradiol (E2) and tamoxifen (Tam) increase the expression of CXCR4 and CXCL12 transcripts and proteins in oestrogen receptor positive (ER(+)) but not in negative (ER(-)02) Ishikawa endometrial adenocarcinoma (ISH) cell lines. However, the demethylating agent 5-Aza-2'-deoxycytidine profoundly elevated CXCR4 and CXCL12 expression in both ER(+) and ER(-)02 ISH cells. Bisulfite sequencing revealed that E2 and Tam up-regulate expression via demethylation of cytosine in the cytosine-guanosine dinucleotide island of CXCR4 and CXCL12 promoters. We also found that E2 and Tam significantly increased, for several hours, the expression of DNA methyltransferase 3B4 enzymatically inactive splice variant in ER(+) but not in ER(-)02 ISH cells. Our results suggest that E2 and Tam, through their ability for gene-transcription regulation, change the cellular milieu that maintains the hypermethylated stage of CpG islands of CXCR4 and CXCL12 promoters.
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PMID:Epigenetic up-regulation of CXCR4 and CXCL12 expression by 17 beta-estradiol and tamoxifen is associated with formation of DNA methyltransferase 3B4 splice variant in Ishikawa endometrial adenocarcinoma cells. 1736 37

It has been recently demonstrated that in colonic carcinoma, CXCL12 expression undergoes epigenetic regulation by methylation of cytosine in cytosine-guanosine (CpG) dinucleotides of the promoter sequence. Using lentiviral vectors, we generated stable RNA interference-mediated knockdown of DNMT1 and DNMT3B in MCF-7 breast cancer and AsPC1 pancreatic carcinoma cell lines. Employing reverse transcription real-time quantitative PCR and immunofluorescence analysis, we determined re-expression levels of CXCL12 transcript and protein in these cells. Bisulfite sequencing revealed that the level of promoter demethylation appeared more effective in cells expressing DNMT1 siRNA than in those expressing DNMT3B siRNA, and this correlated with higher expression of CXCL12. Moreover, the combined expression of DNMT1 and DNMT3B siRNAs enhanced promoter demethylation that was associated only with a slight increase of CXCL12 expression. However, the demethylating agent 5-Aza-2'-deoxycytidine exhibited the strongest effect on promoter demethylation, which correlated with the highest expression level of CXCL12 transcript and protein in MCF-7 and AsPC1 cells. Our findings suggest that DNMT1 plays a key role in maintenance of methylation, and DNMT3B may act as an accessory DNA methyltransferase to epigenetically silence CXCL12 expression in MCF-7 and AsPC1 cells.
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PMID:RNA interference-mediated knockdown of DNMT1 and DNMT3B induces CXCL12 expression in MCF-7 breast cancer and AsPC1 pancreatic carcinoma cell lines. 1753 57

Idiopathic myelofibrosis (IM) is likely the consequence of both the acquisition of genetic mutations and epigenetic changes that silence critical genes that control cell proliferation, differentiation, and apoptosis. We have explored the effects of the sequential treatment with the DNA methyltransferase inhibitor, decitabine [5-aza-2'-deoxycytidine (5azaD)], followed by the histone deacetylase inhibitor, trichostatin A (TSA), on the behavior of IM CD34(+) cells. Unlike normal CD34(+) cells where 5azaD/TSA treatment leads to the expansion of CD34(+) cells and marrow-repopulating cells, treatment of IM CD34(+) cells results in a reduction of the number of total cells, CD34(+) cells, and assayable hematopoietic progenitor cells (HPC). In IM, HPCs are either heterozygous or homozygous for the JAK2V617F mutation or possess wild-type JAK2 in varying proportions. Exposure of IM CD34(+) cells to 5azaD/TSA resulted in a reduction of the proportion of JAK2V617F-positive HPCs in 83% of the patients studied and the reduction in the proportion of homozygous HPCs in 50% of the patients. 5azaD/TSA treatment led to a dramatic reduction in the number of HPCs that contained chromosomal abnormalities in two JAK2V617F-negative IM patients. IM is characterized by constitutive mobilization of HPCs, which has been partly attributed to decreased expression of the chemokine receptor CXCR4. Treatment of IM CD34(+) cells with 5azaD/TSA resulted in the up-regulation of CXCR4 expression by CD34(+) cells and restoration of their migration in response to SDF-1. These data provide a rationale for sequential therapy with chromatin-modifying agents for patients with IM.
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PMID:Effects of chromatin-modifying agents on CD34+ cells from patients with idiopathic myelofibrosis. 1761 2