Peterson Erica J, Bögler Oliver, Taylor Shirley M
Departments of Biology and Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Cancer Res. 2003 Oct 15;63(20):6579-82.
Cytosine methylation patterns in genomic DNA are significantly altered in cancer, and de novo CpG island methylation has been implicated in tumor suppressor gene silencing. Here we demonstrate a mechanistic link between the p53 tumor suppressor gene and control of epigenetic regulation by genomic methylation. Deletion of p53in HCT116 human colon carcinoma cells and primary mouse astrocytes resulted in a 6-fold increase of DNA cytosine methyltransferase 1 (Dnmt1) mRNA and protein, suggesting relief of p53-mediated Dnmt1repression. A p53 consensus binding site in exon 1 of the human Dnmt1gene bound recombinant p53 in vitro and endogenous p53 in vivo in the absence of stimuli that activate p53, implying that p53 controls Dnmt1transcription through direct DNA binding. Interestingly, ionizing radiation or etoposide, both of which stabilize and activate p53, diminished p53 binding in chromatin immunoprecipitation assays, concomitant with a 5-fold increase in Dnmt1 levels. Our findings suggest that activation of p53 reduces binding and relieves transcriptional repression of the Dnmt1gene, whereas loss of p53, a frequent, early event in tumorigenesis, may significantly contribute to aberrant genomic methylation.
癌症中基因组DNA的胞嘧啶甲基化模式会发生显著改变，从头CpG岛甲基化与肿瘤抑制基因沉默有关。在此，我们证明了p53肿瘤抑制基因与基因组甲基化对表观遗传调控的控制之间存在机制联系。在HCT116人结肠癌细胞和原代小鼠星形胶质细胞中缺失p53会导致DNA胞嘧啶甲基转移酶1（Dnmt1）的mRNA和蛋白增加6倍，这表明p53介导的Dnmt1抑制作用得到缓解。在未激活p53的刺激下，人Dnmt1基因外显子1中的一个p53共有结合位点在体外与重组p53结合，在体内与内源性p53结合，这意味着p53通过直接结合DNA来控制Dnmt1转录。有趣的是，电离辐射或依托泊苷（二者均可稳定并激活p53）在染色质免疫沉淀试验中会减少p53的结合，同时Dnmt1水平增加5倍。我们的研究结果表明，p53的激活会减少Dnmt1基因的结合并缓解其转录抑制，而p53的缺失是肿瘤发生中常见的早期事件，可能会显著导致异常的基因组甲基化。
