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)

The DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) has therapeutic value for the treatment of cancer. However, the mechanism by which 5-Aza-CdR induces antineoplastic activity is an important unresolved question. In this study, we found that 5-Aza-CdR at limited concentrations induced inhibition of colorectal cancer Lovo cell proliferation as well as increased apoptosis caused by DNA damage, which was independent of the caspase pathway. Regarding the mechanisms, for the first time, we examined that cytotoxicity against Lovo cells was regulated via down-regulation of DNA methyltransferase 3a, DNMT3b and then reactivated the expression of RUNX3. We therefore conclude that RUNX3 is a relevant target for methyltransferases dependent effects of 5-Aza-CdR on colorectal cancer Lovo cells.
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PMID:5-Aza-2'-deoxycytidine reactivates expression of RUNX3 by deletion of DNA methyltransferases leading to caspase independent apoptosis in colorectal cancer Lovo cells. 1884 67

Aberrant promoter methylation and subsequent silencing of cancer-related genes has been recognized as an important pathway involved in gastric carcinogenesis. In fact, several factors are believed to contribute to its induction in gastric epithelia, including aging, diet, chronic inflammation and infection of Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV). However, the underling mechanisms are not completely identified, despite the belief that increased expression or activity of DNA methyltransferases (DNMTs), or decreased demethylation activity may contribute to the excessive methylation. A great number of genes with promoter methylation have been observed in gastric cancer (GC), among which p16INK4A (p16), Mut L homologue 1 (MLH1), Epithelial-cadherin (E-cadherin), Runt-related transcription factor 3 (RUNX3), adenomatous polyposis coli (APC), O(6)-methylguanine-DNA methyltransferase (MGMT), Ras association domain family 1A (RASSF1A) and Death-associated protein kinase (DAPK) have been extensively studied. Unlike the distinct methylation characterization in single genes, methylation analysis of multiple genes may provide more information in risk prediction, early detection, prognosis assessment and chemotherapy choice for GC. Specifically, particular monitoring and screening should be performed on those over 45 years old, with precancerous gastric disease or infection of H. pylori or EBV. As an alternative to tumor tissues, methylation detection in patient sera or gastric washes may also be used in risk prediction and early detection. However, what still poses a great challenge as well as a puzzle is the determination of the very genes that should be used in methylation analysis. Because epigenetic alterations are normally reversible, drugs or chemical compounds with demethylating activity, such as 5-aza-2'-deoxycytidine (5-aza-dC) could be used in the treatment of patients with multiple gene methylation. In view of the adverse effects of 5-aza-dC, DNMT-targeted strategy has been proposed and may prove to be more effective than demethylating agents.
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PMID:Promoter methylation of tumor-related genes in gastric carcinogenesis. 2293 46

Laryngeal squamous cell carcinoma (LSCC) is a highly aggressive malignant cancer and accounts for 1% to 2% of all malignancies diagnosed worldwide. Runt-related transcription factor 3 (RUNX3), an important tumor suppressor, is known to related to lymph node metastasis and the development of LSCC. However, the biological roles and potential mechanisms RUNX3 expression was not well understood. In this study, we reported that the RUNX3 was significantly downregulated and highly methylated in LSCC compared with their matched normal. The enforced expression of RUNX3 inhibited LSCC cell migration, invasion, and proliferation, whereas the inhibition of RUNX3 did the opposite. We identified that RUNX3 was regulated by miR-148a-3p and found that the expression level of miR-148-3p was significantly decreased and positively related with the expression of RUNX3 in LSCC. We also identified that DNA methyltransferase enzyme DNA (cytosine-5-)-methyltransferase 1 (DNMT1) was targeted by miR-148a-3p in LSCC. The knockdown of DNMT1 promoted the expression of RUNX3 and inhibited migration, invasion, and proliferation in LSCC cells. In summary, our study demonstrated that miR-148a-3p may regulate RUNX3 expression through the modulation of DNMT1-dependent DNA methylation in LSCC, providing a novel target and a potential therapeutic pathway against LSCC. LSCC is a highly aggressive malignant cancer and accounts for 1% to 2% of all malignancies diagnosed worldwide. In this study, we reported that RUNX3, an important tumor suppressor, was significantly downregulated and highly methylated in LSCC compared with their matched normal. The overexpression of RUNX3 inhibited LSCC cell migration, invasion, and proliferation, whereas the inhibition of RUNX3 did the opposite. Moreover, RUNX3 was regulated by miR-148a-3p, which targeted DNA methyltransferase enzyme DNMT1 in LSCC cells. Therefore, miR-148a-3p may regulate RUNX3 expression through the modulation of DNMT1-dependent DNA methylation in LSCC, providing a novel target and a potential therapeutic pathway against LSCC.
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PMID:RUNX3 inhibits laryngeal squamous cell carcinoma malignancy under the regulation of miR-148a-3p/DNMT1 axis. 2785 17

Breast cancer is one of complex diseases that are influenced by environment. Various genetic and epigenetic alterations are provoking causes of breast carcinogenesis. Dynamic epigenetic regulation including DNA methylation and histone modification induces dysregulation of genes related to proliferation, apoptosis, and metastasis in breast cancer. DNA methylation is strongly associated with the repression of transcription through adding to the methyl group by DNA methyltransferases (DNMTs), and tumor suppressor genes such as CCND2 and RUNX3 have been investigated to undergo hypermethylation at promoter region in breast cancer. In addition, histone deacetylases (HDACs) contribute to transcriptional repression by removing acetyl group at lysine residues leading to tumorigenesis. Since epigenetic changes are reversible, therapeutic approaches have been applied with epigenetic modification drugs such as DNMT inhibitors and HDAC inhibitors. In this chapter, we will summarize the feature of epigenetic markers in breast cancer cells and the effect of single or combination of epigenetic reagents for breast cancer therapy.
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PMID:Targeting the Epigenome as a Novel Therapeutic Approach for Breast Cancer. 2928 90

Myocardial infarction (MI) is a major contributor to death and disability throughout the world. Increasing evidence shows that long noncoding RNAs (lncRNAs) are involved in the progression of MI. Here, we hypothesized that lncRNA potassium voltage-gated channel subfamily q member 1 overlapping transcript 1 (KCNQ1OT1) could affect the development of MI via regulation of Runt-related transcription factor (RUNX)3 by methylation. Initially, by ligation of the left anterior descending coronary artery, an acute MI (AMI) mouse model was established to collect the cardiac microvascular endothelial cells (CMECs), which revealed a high KCNQ1OT1 expression and a low RUNX3 expression with its high methylation. After that, KCNQ1OT1 knockdown or RUNX3 overexpression were transduced into the CMECs in order to detect their role in CMEC proliferation, apoptosis, and inflammatory response. Moreover, we assessed their interaction with the inflammatory Notch pathway, by determining the expression of Jagged 1, Hey1, Hes1, Notch intracellular domain, and Notch1. It was observed that after KCNQ1OT1 knockdown, the proliferation of AMI-CMECs was promoted, whereas their apoptosis was inhibited, accompanied by reduced level of inflammatory factors. These trends could also be achieved by RUNX3 overexpression via the Notch pathway. Finally, the regulation of DNA methyltransferase (DNMT)1-dependent methylation in RUNX3 by KCNQ1OT1 was determined, suggesting that KCNQ1OT1 could result in down-regulated RUNX3 expression through promoted RUNX3 methylation caused by recruiting DNMT1. Overall, this study demonstrates that KCNQ1OT1 silencing inhibits RUNX3 methylation, thereby offering protection against CMEC injury and inflammatory response in AMI, which may serve as a promising target for the disease treatment. -Wang, Y., Yang, X., Jiang, A., Wang, W., Li, J., Wen, J. Methylation-dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction.
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PMID:Methylation-dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction. 3162 14