Centre for Rare Diseases and Personalized Medicine, University of Birmingham, Birmingham, UK.
Epigenetics. 2012 Mar;7(3):278-90. doi: 10.4161/epi.7.3.19103.
In order to identify novel candidate tumor suppressor genes (TSGs) implicated in renal cell carcinoma (RCC), we performed genome-wide methylation profiling of RCC using the HumanMethylation27 BeadChips to assess methylation at > 14,000 genes. Two hundred and twenty hypermethylated probes representing 205 loci/genes were identified in genomic CpG islands. A subset of TSGs investigated in detail exhibited frequent tumor methylation, promoter methylation associated transcriptional silencing and reactivation after demethylation in RCC cell lines and down-regulation of expression in tumor tissue (e.g., SLC34A2 specifically methylated in 63% of RCC, OVOL1 in 40%, DLEC1 in 20%, TMPRSS2 in 26%, SST in 31% and BMP4 in 35%). As OVOL1, a putative regulator of c-Myc transcription, and SST (somatostatin) had not previously been linked to cancer and RCC, respectively, we (1) investigated their potential relevance to tumor growth by RNAi knockdown and found significantly increased anchorage-independent growth and (2) demonstrated that OVOL1 knockdown increased c-Myc mRNA levels.
为了鉴定与肾细胞癌（RCC）相关的新型候选肿瘤抑制基因（TSG），我们使用 HumanMethylation27 BeadChips 对 RCC 进行了全基因组甲基化谱分析，以评估超过 14000 个基因的甲基化情况。在基因组 CpG 岛中鉴定出 220 个呈高甲基化的探针，代表 205 个基因座/基因。经过详细研究的 TSG 子集表现出频繁的肿瘤甲基化、启动子甲基化导致转录沉默以及在 RCC 细胞系中去甲基化后的重新激活，并且在肿瘤组织中表达下调（例如，SLC34A2 在 63%的 RCC 中特异性甲基化，OVOL1 在 40%，DLEC1 在 20%，TMPRSS2 在 26%，SST 在 31%，BMP4 在 35%）。由于 OVOL1 是 c-Myc 转录的潜在调节因子，而 SST（生长抑素）分别以前与癌症和 RCC 没有联系，因此我们：1）通过 RNAi 敲低研究了它们与肿瘤生长的潜在相关性，发现锚定非依赖性生长显著增加；2）证明 OVOL1 敲低增加了 c-Myc mRNA 水平。
