Dysregulation of p53/Sp1 Control Leads to DNA Methyltransferase-1 Overexpression in Lung Cancer
Dysregulation of p53/Sp1 Control Leads to DNA Methyltransferase-1 Overexpression in Lung Cancer
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DOI：
10.1158/0008-5472.can-09-4161
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Yi-Ching
中科院分区：
文献类型：
--
作者：
Lin, Ruo-Kai;Wu, Chiu-Yi;Wang, Yi-Ching
DNA 5 '-胞嘧啶甲基转移酶（DNMT）是使CpG的胞嘧啶残基甲基化的酶，其过表达涉及许多癌症。然而，DNMT过表达的机制仍不清楚。在这里，我们表明，野生型p53负调控DNMT 1的表达，形成一个复合物与特异性蛋白1（Sp1）蛋白和染色质修饰剂的DNMT 1启动子。然而，p53和Sp1之间的化学计量决定了Sp1是否作为转录激活因子或辅阻遏物。低水平的外源性Sp1增强内源性p53对DNMT 1启动子的抑制活性，而高水平的Sp1上调A549（p53野生型）细胞中DNMT 1基因的表达水平。在H1299（p53 null）细胞中，外源性Sp1以剂量依赖性方式诱导DNMT 1表达。我们还发现了一种新的机制，即高水平的Sp1，通过其COOH末端结构域，诱导p53和MDM 2之间的相互作用，导致通过MDM 2介导的泛素化降解p53。102例肺癌患者的临床资料表明，DNMT 1的过度表达与p53突变（P = 0.014）和Sp1蛋白的高表达（P = 0.006）有关。此外，DNMT 1和Sp1蛋白均过表达的患者预后较差（P = 0.037）。我们的细胞和临床数据提供了令人信服的证据表明，DNMT 1的失调与Sp1转录激活的获得和/或p53抑制的丧失有关。DNMT 1过表达导致多个肿瘤抑制基因的表观遗传学改变，并最终导致肺肿瘤的发生和不良预后。癌症研究; 70（14）; 5807-17。（C）2010年AACR。
Overexpression of DNA 5'-cytosine-methyltransferases (DNMT), which are enzymes that methylate the cytosine residue of CpGs, is involved in many cancers. However, the mechanism of DNMT overexpression remains unclear. Here, we showed that wild-type p53 negatively regulated DNMT1 expression by forming a complex with specificity protein 1 (Sp1) protein and chromatin modifiers on the DNMT1 promoter. However, the stoichiometry between p53 and Sp1 determined whether Sp1 acts as a transcription activator or corepressor. Low level of exogenous Sp1 enhanced the repressive activity of endogenous p53 on the DNMT1 promoter whereas high level of Sp1 upregulated DNMT1 gene expression level in A549 (p53 wild-type) cells. In H1299 (p53 null) cells, exogenous Sp1 induced DNMT1 expression in a dose-dependent manner. We also discovered a new mechanism whereby high level of Sp1, via its COOH-terminal domain, induced interaction between p53 and MDM2, resulting in degradation of p53 by MDM2-mediated ubiquitination. Clinical data from 102 lung cancer patients indicated that overexpression of DNMT1 was associated with p53 mutation (P = 0.014) and high expression of Sp1 protein (P = 0.006). In addition, patients with overexpression of both DNMT1 and Sp1 proteins showed poor prognosis (P = 0.037). Our cell and clinical data provided compelling evidence that deregulation of DNMT1 is associated with gain of transcriptional activation of Sp1 and/or loss of repression of p53. DNMT1 overexpression results in epigenetic alteration of multiple tumor suppressor genes and ultimately leads to lung tumorigenesis and poor prognosis. Cancer Res; 70(14); 5807-17. (C)2010 AACR.