Effects of specific DNMT gene depletion on cancer cell transformation and breast cancer cell invasion; toward selective DNMT inhibitors
Effects of specific DNMT gene depletion on cancer cell transformation and breast cancer cell invasion; toward selective DNMT inhibitors
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DOI：
10.1093/carcin/bgq221
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发表时间：
2011-02-01
期刊：
影响因子：
4.7
通讯作者：
Szyf, Moshe
中科院分区：
文献类型：
--
作者：
Chik, Flora;Szyf, Moshe
癌症的一个标志是异常的DNA甲基化，包括肿瘤抑制基因的整体低甲基化和区域高甲基化。DNA甲基转移酶抑制剂已被公认为是有前途的候选抗癌药物。药物开发集中在DNA甲基化抑制剂上，其目标是激活被DNA甲基化沉默的肿瘤抑制基因。5-氮杂胞苷（5-AC;维达扎），一种全球性的DNA甲基转移酶抑制剂，被美国食品和药物管理局批准用于治疗骨髓增生异常综合征，并进行了实体瘤的临床试验。在这篇论文中，证明了5-azaCdR通过去甲基化激活了沉默的肿瘤抑制基因和促转移基因，引起了人们对它会促进转移的关注。5-AzaCdR处理增加了非侵袭性乳腺癌细胞系MCF-7细胞和ZR-75-1的侵袭力，并显著诱导了促转移基因;尿激酶纤溶酶原激活物（uPA）、基质金属蛋白酶2（MMP 2）、转移相关基因（H-MTS 1; S100 A4）和C-X-C趋化因子受体4（CXCR 4）。使用靶向不同DNA甲基转移酶（DNMT）基因的短干扰RNA（siRNA）测试DNA甲基转移酶抑制剂的细胞转化活性的阻断可以与促转移活性分离的假设。尽管在细胞转化试验中DNMT 1的缺失对集落生长抑制具有最强的作用，但它并不导致MCF-7细胞中uPA、S100 A4、MMP 2和CXCR 4的去甲基化和活化。DNMT 1的缺失在MCF-7和ZR-75-1非侵袭性乳腺癌细胞系中不诱导细胞侵袭。这些数据的设计新的DNA甲基转移酶抑制剂和正确利用现有的抑制剂的影响。
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.