Methylation associated transcriptional repression of ELOVL5 in novel colorectal cancer cell lines
Methylation associated transcriptional repression of ELOVL5 in novel colorectal cancer cell lines
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DOI：
10.1371/journal.pone.0184900
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发表时间：
2017-09-20
期刊：
影响因子：
3.7
通讯作者：
van Wezel, Tom
中科院分区：
文献类型：
--
作者：
Boot, Arnoud;Oosting, Jan;van Wezel, Tom
基因和表观遗传改变标志着结直肠癌(CRC)。几乎所有的结直肠癌都观察到全局性低甲基化，但结直肠癌的一个不同亚群表现为CpG岛甲基化表型(CIMP)。这些肿瘤表现为CpG岛的一个特定子集的DNA高度甲基化，导致附近基因的转录下调。最近，我们报道了从原发和转移的结直肠癌组织中建立新的结直肠癌细胞系。在这项研究中，我们描述了这些低传代结直肠癌细胞系的DNA甲基化图谱。我们用InfiniumHumanMetylation450珠芯片生成了全球DNA甲基化图谱，并结合匹配的基因表达图谱进行了分析。DNA甲基化和基因表达数据集的多维缩放显示，BRAF突变的细胞系形成了一个不同的组。在这个小组中，我们研究了之前在BRAF突变体CRC中发现的706个高甲基化的基因座。我们验证了癌症基因组图谱结肠腺癌数据集中的重要发现。我们的分析发现ELOVL5、FAM127B、MTERF1、ZNF606在结直肠癌中通过DNA高甲基化而受到转录下调的影响。我们进一步用qPCR和免疫组织化学染色检测了ELOVL5，验证了我们的结果，但没有发现ELOVL5的表达与肿瘤分期或无复发生存期之间的明显关系。ELOVL5、FAM127B、MTERF1、ZNF606参与了重要的细胞过程，如细胞凋亡、脂肪生成和MAPK途径的下游转录效应等。我们已经确定了在结直肠癌中调节关键细胞过程的DNA甲基化特征，从而对肿瘤细胞产生生长优势。
Genetic and epigenetic alterations mark colorectal cancer (CRC). Global hypomethylation is observed in nearly all CRC, but a distinct subset of CRC show the CpG Island Methylator Phenotype (CIMP). These tumors show DNA hypermethylation of a specific subset of CpG islands, resulting in transcriptional downregulation of nearby genes. Recently we reported the establishment of novel CRC cell lines derived from primary and metastatic CRC tissues. In this study we describe the DNA methylation profiling of these low passage CRC cell lines. We generated global DNA methylation profiles with Infinium HumanMethylation450 Bead-Chips and analysed them in conjunction with matching gene expression profiles. Multidimensional scaling of the DNA methylation and gene expression datasets showed that BRAF mutated cell lines form a distinct group. In this group we investigated the 706 loci which we have previously identified to be hypermethylated in BRAF mutant CRC. We validated the significant findings in the The Cancer Genome Atlas colon adenocarcinoma data-set. Our analysis identified ELOVL5, FAM127B, MTERF1, ZNF606 to be subject to transcriptional downregulation through DNA hypermethylation in CRC. We further investigated ELOVL5 with qPCR and immunohistochemical staining, validating our results, but did not find a clear relation between ELOVL5 expression and tumor stage or relapse free survival. ELOVL5, FAM127B, MTERF1, ZNF606 are involved in important cellular processes such as apoptosis, lipogenesis and the downstream transcriptional effect of the MAPK-pathway. We have identified a DNA methylation profile regulating key cellular processes in CRC, resulting in a growth advantage to the tumor cells.