Epigallocatechin-3-gallate up-regulates tumor suppressor gene expression via a reactive oxygen species-dependent down-regulation of UHRF1
Epigallocatechin-3-gallate up-regulates tumor suppressor gene expression via a reactive oxygen species-dependent down-regulation of UHRF1
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DOI：
10.1016/j.bbrc.2012.11.087
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发表时间：
2013-01-04
影响因子：
3.1
通讯作者：
Bronner, Christian
中科院分区：
文献类型：
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作者：
Achour, Mayada;Mousli, Marc;Bronner, Christian
含有类泛素的PHD和环指1（UHRF 1）通过将DNA甲基转移酶I（DNMT 1）募集到它们的半甲基化启动子中而有助于肿瘤抑制基因的沉默。相反，这些启动子的去甲基化被归因于天然抗癌药物表没食子儿茶素-3-没食子酸酯（epigallocatechin-3-gallate，EGCG）。本研究的目的是调查UHRF 1/DNMT 1对是否是EGCG作用的重要靶点。在这里，我们发现，EGCG下调Jurkat细胞中UHRF 1和DNMT 1的表达，随后上调p73和p16（INK 4A）基因。UHRF 1的下调依赖于EGCG产生的活性氧。p16（INK 4A）的上调与UHRF 1的启动子结合减少密切相关。UHRF 1的过度表达抵消了EGCG诱导的G1期阻滞细胞、细胞凋亡以及p16（INK 4A）和p73的上调。UHRF 1的集合和环相关（SRA）结构域的突变体不能下调p16（INK 4A）和p73，无论是在存在或不存在的EGCG。我们的研究结果表明，UHRF 1的下调是上游的许多细胞事件，包括G1期细胞阻滞，肿瘤抑制基因的上调和凋亡。(C)2012 Elsevier Inc. All rights reserved.
Ubiquitin-like containing PHD and Ring finger 1 (UHRF1) contributes to silencing of tumor suppressor genes by recruiting DNA methyltransferase I (DNMT1) to their hemi-methylated promoters. Conversely, demethylation of these promoters has been ascribed to the natural anti-cancer drug, epigallocatechin-3-gallate (EGCG). The aim of the present study was to investigate whether the UHRF1/DNMT1 pair is an important target of EGCG action. Here, we show that EGCG down-regulates UHRF1 and DNMT1 expression in Jurkat cells, with subsequent up-regulation of p73 and p16(INK4A) genes. The down-regulation of UHRF1 is dependent upon the generation of reactive oxygen species by EGCG. Up-regulation of p16(INK4A) is strongly correlated with decreased promoter binding by UHRF1. UHRF1 over-expression counteracted EGCG-induced G1-arrested cells, apoptosis, and up-regulation of p16(INK4A) and p73. Mutants of the Set and Ring Associated (SRA) domain of UHRF1 were unable to down-regulate p16(INK4A) and p73, either in the presence or absence of EGCG. Our results show that down-regulation of UHRF1 is upstream to many cellular events, including G1 cell arrest, up-regulation of tumor suppressor genes and apoptosis. (C) 2012 Elsevier Inc. All rights reserved.