Methyl-CpG targeted recruitment of p300 reactivates tumor suppressor genes in human cancer cells
Methyl-CpG targeted recruitment of p300 reactivates tumor suppressor genes in human cancer cells
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DOI：
10.1016/j.bbrc.2009.01.010
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发表时间：
2009-02-20
影响因子：
3.1
通讯作者：
Horii, Akira
中科院分区：
文献类型：
--
作者：
Fukushige, Shinichi;Kondo, Emiko;Horii, Akira
基因启动子异常高甲基化是癌症中肿瘤抑制基因（TSGs）失活的主要机制。我们之前已经表明，甲基化cpg靶向转录激活（MeTA）允许TSGs在人类癌细胞中重新表达，通过甲基化cpg结合域（MBD）和NF κ B转录激活域（AD）结合，伴随着组蛋白H3K9/K14乙酰化。在这里，我们证明p300组蛋白乙酰转移酶（HAT）是NF κ B （AD）相关的共激活因子之一，可以在293T细胞中重新激活表观遗传沉默的MLH1。有趣的是，p300的HAT结构域对于MLH1的再激活不是必需的；相反，c端转激活结构域（C-TAD）而不是n端转激活结构域（N-TAD）重新激活MLH1。此外，在三种类型的癌细胞中分析的所有10个癌症相关基因都被与MBD相关的p300的作用重新激活。这些结果表明，通过直接靶向高度甲基化启动子的转录辅激活子，可以重新激活人类癌细胞中表观遗传沉默的TSGs。版权所有(C) 2009 Elsevier Inc版权所有。
Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor suppressor genes (TSGs) in cancer, We have previously shown that the methyl-CpG targeted transcriptional activation (MeTA) that allows re-expression of TSGs in human cancer cells is accomplished by combining a methyl-CpG binding domain (MBD) with a NF kappa B transcriptional activation domain (AD), accompanied by histone H3K9/K14 acetylation, Herein we demonstrate that p300 histone acetyltransferase (HAT), one of the NF kappa B (AD)-associated coactivators, reactivates epigenetically silenced MLH1 in 293T cells. Interestingly, the HAT domain of p300 is not essential for the reactivation of MLH1; instead, the C-terminal transactivation domain (C-TAD) but not the N-terminal one (N-TAD) reactivates MLH1. Furthermore, all ten of the cancer-related genes analyzed in three types of cancer cells were reactivated by the effect of p300 linked to MBD. These results demonstrate that it is possible to reactivate epigenetically silenced TSGs in human cancer cells by direct targeting of a transcriptional coactivator at highly methylated promoters. All rights reserved (C) 2009 Elsevier Inc. All rights reserved.