Expression of metastasis suppressor gene AES driven by a Yin Yang (YY) element in a CpG island promoter and transcription factor YY2.
Expression of metastasis suppressor gene AES driven by a Yin Yang (YY) element in a CpG island promoter and transcription factor YY2.
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DOI：
10.1111/cas.13063
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发表时间：
2016-11
期刊：
影响因子：
5.7
通讯作者：
Taketo MM
中科院分区：
文献类型：
--
作者：
Kakizaki F;Sonoshita M;Miyoshi H;Itatani Y;Ito S;Kawada K;Sakai Y;Taketo MM
我们最近发现，AES基因的产物在人类和小鼠身上都具有结直肠癌转移抑制因子的功能。肝转移瘤组织中分裂氨基末端增强子(AES)蛋白的表达明显低于原发灶。为了研究其在转移中的下调机制，我们搜索了人结直肠癌中AES的转录调控因子，发现其表达主要通过转录调控失调，在某些情况下，通过其编码基因的额外单倍化而降低。该启动子-增强子位于典型的CpG岛上，含有一个阴阳转录因子识别序列(YY元件)。在人类正常结肠和原发肿瘤的上皮细胞中，转录因子YY2是YY家族的成员，它直接与YY元件结合，并刺激AES的表达。然而，在肝转移的移植小鼠模型中，Yy2(因此也就是AES)的表达下调。在人肝转移癌中，AES蛋白表达水平与YY2蛋白表达水平呈正相关。此外，在12%(5/42)的人结直肠癌细胞系中，我们注意到染色体19p13.3上的AES编码基因的拷贝数减少。我们排除了其他机制，如AES基因编码区或调控区的点突变或内突变，AES启动子增强子的CpG甲基化，microRNAs的表达，以及染色质组蛋白的修饰。这些结果表明，AES可能属于一个新的带有CpG岛启动子增强子的转移抑制基因家族，并且它受转录调控。
We recently found that the product of the AES gene functions as a metastasis suppressor of colorectal cancer (CRC) in both humans and mice. Expression of amino‐terminal enhancer of split (AES) protein is significantly decreased in liver metastatic lesions compared with primary colon tumors. To investigate its downregulation mechanism in metastases, we searched for transcriptional regulators of AES in human CRC and found that its expression is reduced mainly by transcriptional dysregulation and, in some cases, by additional haploidization of its coding gene. The AES promoter‐enhancer is in a typical CpG island, and contains a Yin‐Yang transcription factor recognition sequence (YY element). In human epithelial cells of normal colon and primary tumors, transcription factor YY2, a member of the YY family, binds directly to the YY element, and stimulates expression of AES. In a transplantation mouse model of liver metastases, however, expression of Yy2 (and therefore of Aes) is downregulated. In human CRC metastases to the liver, the levels of AES protein are correlated with those of YY2. In addition, we noticed copy‐number reduction for the AES coding gene in chromosome 19p13.3 in 12% (5/42) of human CRC cell lines. We excluded other mechanisms such as point or indel mutations in the coding or regulatory regions of the AES gene, CpG methylation in the AES promoter enhancer, expression of microRNAs, and chromatin histone modifications. These results indicate that Aes may belong to a novel family of metastasis suppressors with a CpG‐island promoter enhancer, and it is regulated transcriptionally.
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影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
3.7
作者：
Knutsen, T;Gobu, V;Ried, T
通讯作者：
Ried, T
DOI：
10.1073/pnas.0712345105
发表时间：
2008-03-18
影响因子：
11.1
作者：
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通讯作者：
Markowitz, Sanford D.
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
14.9
作者：
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通讯作者：
GUSTAFSSON, P