BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer.
BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer.
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发表时间：
2013
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通讯作者：
Petra A. Link;Wa Zhang;K. Odunsi;A. Karpf
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作者：
Petra A. Link;Wa Zhang;K. Odunsi;A. Karpf
癌症种系（CG）基因通常在生殖细胞中表达，在多种癌症中异常表达；它们的免疫原性促使针对这些抗原的癌症疫苗得到广泛开发。BORIS/CTCFL是一种常染色体CG抗原，是很有前景的癌症疫苗靶点。BORIS是CTCF唯一已知的旁系同源物，CTCF是一个与基因组印记、染色质绝缘和核调控密切相关的基因。我们先前已经表明，BORIS在上皮性卵巢癌（EOC）中表达，并且其表达与启动子和整体DNA低甲基化同时发生。最近，已经描述了23种不同的BORIS mRNA变体，并在功能上分为6个BORIS异构体家族（sf1 - sf6）。在本研究中，我们对BORIS异构体家族在正常卵巢（NO）和EOC中的表达进行了表征，选择的EOC包括两组整体DNA甲基化状态差异很大的样本。我们发现BORIS异构体家族在NO中选择性表达，在EOC中发生改变，主要是由于BORIS sf1在EOC中被激活。当根据甲基化状态比较EOC样本时，我们发现BORIS sf1和sf2异构体家族在整体低甲基化的肿瘤中被选择性激活。相比之下，CTCF在EOC中下调，并且BORIS sf1、sf2和sf6异构体家族与CTCF的比值在低甲基化肿瘤中升高。最后，在EOC细胞系中，表观遗传调节药物在不同程度上诱导了所有BORIS异构体家族的表达，特别是当DNA甲基转移酶（DNMT）和组蛋白去乙酰化酶（HDAC）抑制剂联合使用时。
Cancer germline (CG) genes are normally expressed in germ cells and aberrantly expressed in a variety of cancers; their immunogenicity has led to the widespread development of cancer vaccines targeting these antigens. BORIS/CTCFL is an autosomal CG antigen and promising cancer vaccine target. BORIS is the only known paralog of CTCF, a gene intimately involved in genomic imprinting, chromatin insulation, and nuclear regulation. We have previously shown that BORIS is expressed in epithelial ovarian cancer (EOC) and that its expression coincides with promoter and global DNA hypomethylation. Recently, 23 different BORIS mRNA variants have been described, and have been functionally grouped into six BORIS isoform families (sf1-sf6). In the present study, we have characterized the expression of BORIS isoform families in normal ovary (NO) and EOC, the latter of which were selected to include two groups with widely varying global DNA methylation status. We find selective expression of BORIS isoform families in NO, which becomes altered in EOC, primarily by the activation of BORIS sf1 in EOC. When comparing EOC samples based on methylation status, we find that BORIS sf1 and sf2 isoform families are selectively activated in globally hypomethylated tumors. In contrast, CTCF is downregulated in EOC, and the ratio of BORIS sf1, sf2, and sf6 isoform families as a function of CTCF is elevated in hypomethylated tumors. Finally, the expression of all BORIS isoform families was induced to varying extents by epigenetic modulatory drugs in EOC cell lines, particularly when DNMT and HDAC inhibitors were used in combination.