Metallothionein 1E is methylated in malignant melanoma and increases sensitivity to cisplatin-induced apoptosis
Metallothionein 1E is methylated in malignant melanoma and increases sensitivity to cisplatin-induced apoptosis
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DOI：
10.1097/cmr.0b013e32833d32a6
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发表时间：
2010-10-01
影响因子：
2.2
通讯作者：
Gallagher, William M.
中科院分区：
文献类型：
--
作者：
Faller, William J.;Rafferty, Mairin;Gallagher, William M.
DNA甲基化通过沉默肿瘤抑制基因在癌症中起主要作用。到目前为止，在黑色素瘤中只发现了离散数量的甲基化基因。在用DNA甲基转移酶抑制剂处理黑色素瘤细胞和随后的转录组学分析后，我们已经在早期确定了一组受甲基化调控的黑色素瘤进展相关基因。在这里，我们确定了这些基因中的哪些在黑色素瘤细胞系和组织中直接甲基化。首先，我们在WM 793等基因细胞系模型系列中通过亚硫酸氢盐测序检查了16个基因。其中5个基因（CYBA，FABP 5，MT 1 E，TSPY 1和TAC 1）在几种侵袭性细胞系中与亲本WM 793细胞相比显示出甲基化增加，表明它们参与了进展。接下来，我们使用甲基化特异性PCR分析了几种匹配的原发性/转移性肿瘤，结果显示MT 1 E（评估的五种基因之一）在最大比例的肿瘤中被甲基化。对较大样本队列的检查显示，17例良性痣中有1例（6%）、43例原发性肿瘤中有16例（37%）和13例转移瘤中有6例（46%）显示MT 1 E甲基化。此外，MT 1 E的异位过表达介导了对顺铂诱导的细胞凋亡的敏感性。总的来说，这些研究表明，MT 1 E是一个潜在的肿瘤抑制基因，其丢失可能会促进对肿瘤诱导疗法的抵抗。黑色素瘤研究20：392-400（C）2010年威科健康|利平科特威廉姆斯&威尔金斯。
DNA methylation plays a major role in cancer by silencing tumour suppressor genes. In melanoma, only a discrete number of methylated genes have been identified so far. After the treatment of melanoma cells with a DNA methyltransferase inhibitor and subsequent transcriptomic profiling, we had identified earlier a cohort of melanoma progression-associated genes regulated by methylation. Here, we identified which of these genes are directly methylated in melanoma cell lines and tissues. First, we examined 16 genes by bisulphite sequencing in the WM793 isogenic cell line model series. Five of these genes (CYBA, FABP5, MT1E, TSPY1 and TAC1) displayed increased methylation in several invasive cell lines compared with the parental WM793 cells, indicating their involvement in progression. Next, we analyzed several matched primary/metastatic tumours using methylation-specific PCR, which revealed that MT1E (one of the five genes assessed) was methylated in the largest proportion of tumours. Examination of a larger cohort of samples showed that 1 of 17 (6%) of the benign naevi, 16 of 43 (37%) primary tumours and 6 of 13 (46%) of the metastases displayed MT1E methylation. In addition, ectopic over-expression of MT1E mediated sensitization to cisplatin-induced apoptosis. Overall, these studies suggest that MT1E is a potential tumour suppressor gene, whose loss may promote resistance to apoptosis-inducing therapies. Melanoma Res 20: 392-400 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.