Effects of specific DNMT gene depletion on cancer cell transformation and breast cancer cell invasion; toward selective DNMT inhibitors
| Autor: | Moshe Szyf, Flora Chik |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Cancer Research Small interfering RNA DNA Methyltransferase Inhibitor Breast Neoplasms Biology medicine.disease_cause DNA methyltransferase DNA Methyltransferase 3A Cell Line Tumor medicine Humans Neoplasm Invasiveness DNA (Cytosine-5-)-Methyltransferases Enzyme Inhibitors Cancer General Medicine DNA Methylation medicine.disease Urokinase-Type Plasminogen Activator Cell Transformation Neoplastic DNA methylation Cancer cell DNMT1 Cancer research Female Carcinogenesis Gene Deletion |
| Zdroj: | Carcinogenesis. 32(2) |
| ISSN: | 1460-2180 |
| Popis: | A hallmark of cancer is aberrant DNA methylation, consisting of global hypomethylation and regional hypermethylation of tumor suppressor genes. DNA methyltransferase inhibitors have been recognized as promising candidate anticancer drugs. Drug development has focused on DNA methylation inhibitors with the goal of activating tumor suppressor genes silenced by DNA methylation. 5-azacytidine (5-AC; Vidaza), a global DNA methyltransferase inhibitor, was Food and Drug Administration approved to treat myelodysplastic syndromes and is clinically tested for solid tumors. In this paper, it was demonstrated that 5'-aza-2'-deoxycytidine (5-azaCdR) activated both silenced tumor suppressor genes and pro-metastatic genes by demethylation, raising the concern that it would promote metastasis. 5-AzaCdR treatment increased the invasiveness of non-invasive breast cancer cell lines MCF-7 cells and ZR-75-1 and dramatically induced pro-metastatic genes; Urokinase plasminogen activator (uPA), matrix metalloproteinase 2 (MMP2), metastasis-associated gene (H-MTS1; S100A4) and C-X-C chemokine receptor 4 (CXCR4). The hypothesis that the blocking of cellular transformation activity of DNA methyltransferase inhibitor could be separated from the pro-metastatic activity was tested using short interfering RNA (siRNA) targeted to the different DNA methyltransferase (DNMT) genes. Although depletion of DNMT1 had the strongest effect on colony growth suppression in cellular transformation assays, it did not result in demethylation and activation of uPA, S100A4, MMP2 and CXCR4 in MCF-7 cells. Depletion of DNMT1 did not induce cellular invasion in MCF-7 and ZR-75-1 non-invasive breast cancer cell lines. These data have implications on the design of new DNA methyltransferase inhibitor and on the proper utilization of current inhibitors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|