Tsuji T, Usui S, Aida T, Tachikawa T, Hu G F, Sasaki A, Matsumura T, Todd R, Wong D T
Department of Oral Medicine and Diagnostic Sciences, Division of Oral Pathology, Harvard School of Dental Medicine, Boston, Massachusetts, MA 02115, USA.
Oncogene. 2001 Jan 4;20(1):24-33. doi: 10.1038/sj.onc.1204051.
The hamster ornithine decarboxylase antizyme (ODC-Az) cDNA was transfected into the hamster malignant oral keratinocyte cell line, HCPC-1. Ectopic expression of ODC-Az resulted in the reversion of malignant phenotypes and alteration of DNA methylation status of CCGG sites. The phenotypes examined include ODC enzymatic activity, doubling time, morphological change, anchorage dependent growth, tumorigenicity in nude mice, induction of epithelial differentiation marker protein (involucrin), and change of cell cycle position. Comparison of CCGG DNA methylation status of the ODC-Az and control vector transfectants revealed a significant increase in demethylation of 5-methyl cytosines (m5C) of CCGG sites in the ODC-Az transfectants. Ectopic expression of ODC-Az gene in hamster malignant oral keratinocytes led to reduce ODC activity and the subsequent demethylation of 5-methyl cytosines, presumably via the ODC/ polyamines/ decarboxylated S-adenosylmethionine (dc-AdoMet) pathways. Our data suggest that ODC-Az shared the same pathway of polyamines/ dc-AdoMet/DNA methyltransferase (DNA MTase). We propose that ODC-Az mediates a novel mechanism in tumor suppression by DNA demethylation and presumably re-activation of key cellular genes silenced by DNA hypermethylation during cancer development. Oncogene (2001) 20, 24 - 33.
将仓鼠鸟氨酸脱羧酶抗酶（ODC-Az）cDNA转染至仓鼠恶性口腔角质形成细胞系HCPC-1中。ODC-Az的异位表达导致恶性表型逆转以及CCGG位点DNA甲基化状态改变。所检测的表型包括ODC酶活性、倍增时间、形态变化、贴壁依赖性生长、裸鼠致瘤性、上皮分化标记蛋白（内披蛋白）的诱导以及细胞周期位置的改变。对ODC-Az和对照载体转染子的CCGG DNA甲基化状态进行比较发现，ODC-Az转染子中CCGG位点的5-甲基胞嘧啶（m5C）去甲基化显著增加。仓鼠恶性口腔角质形成细胞中ODC-Az基因的异位表达导致ODC活性降低以及随后5-甲基胞嘧啶的去甲基化，推测是通过ODC/多胺/脱羧S-腺苷甲硫氨酸（dc-AdoMet）途径。我们的数据表明ODC-Az与多胺/dc-AdoMet/DNA甲基转移酶（DNA MTase）具有相同的途径。我们提出ODC-Az通过DNA去甲基化介导一种新的肿瘤抑制机制，并且可能重新激活癌症发生过程中因DNA高甲基化而沉默的关键细胞基因。《癌基因》（2001年）第20卷，第24 - 33页
