Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Birmingham, UK.
Oncogene. 2010 Apr 8;29(14):2104-17. doi: 10.1038/onc.2009.493. Epub 2010 Feb 15.
Promoter region hyermethylation and transcriptional silencing is a frequent cause of tumour suppressor gene (TSG) inactivation in many types of human cancers. Functional epigenetic studies, in which gene expression is induced by treatment with demethylating agents, may identify novel genes with tumour-specific methylation. We used high-density gene expression microarrays in a functional epigenetic study of 11 renal cell carcinoma (RCC) cell lines. Twenty-eight genes were then selected for analysis of promoter methylation status in cell lines and primary RCC. Eight genes (BNC1, PDLIM4, RPRM, CST6, SFRP1, GREM1, COL14A1 and COL15A1) showed frequent (>30% of RCC tested) tumour-specific promoter region methylation. Hypermethylation was associated with transcriptional silencing. Re-expression of BNC1, CST6, RPRM and SFRP1 suppressed the growth of RCC cell lines and RNA interference knock-down of BNC1, SFRP1 and COL14A1 increased the growth of RCC cell lines. Methylation of BNC1 or COL14A1 was associated with a poorer prognosis independent of tumour size, stage or grade. The identification of these epigenetically inactivated candidate RCC TSGs can provide insights into renal tumourigenesis and a basis for developing novel therapies and biomarkers for prognosis and detection.
启动子区域的高甲基化和转录沉默是许多类型人类癌症中肿瘤抑制基因（TSG）失活的常见原因。功能表观遗传学研究，通过用去甲基化剂处理来诱导基因表达，可能会鉴定出具有肿瘤特异性甲基化的新基因。我们在对 11 个肾细胞癌（RCC）细胞系进行的功能表观遗传学研究中使用了高密度基因表达微阵列。然后选择 28 个基因来分析细胞系和原发性 RCC 中的启动子甲基化状态。有 8 个基因（BNC1、PDLIM4、RPRM、CST6、SFRP1、GREM1、COL14A1 和 COL15A1）表现出频繁的（超过 30%的 RCC 检测到）肿瘤特异性启动子区域甲基化。高甲基化与转录沉默有关。BNC1、CST6、RPRM 和 SFRP1 的重新表达抑制了 RCC 细胞系的生长，而 BNC1、SFRP1 和 COL14A1 的 RNA 干扰敲低则增加了 RCC 细胞系的生长。BNC1 或 COL14A1 的甲基化与肿瘤大小、分期或分级无关的预后不良有关。这些表观遗传失活的候选 RCC TSG 的鉴定可以深入了解肾肿瘤发生，并为开发新的治疗方法和预后及检测的生物标志物提供依据。
