Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation.
Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation.
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DOI：
10.1371/journal.pone.0053003
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Spinella MJ
中科院分区：
文献类型：
--
作者：
Biswal BK;Beyrouthy MJ;Hever-Jardine MP;Armstrong D;Tomlinson CR;Christensen BC;Marsit CJ;Spinella MJ
人胚胎癌（EC）细胞是非精原细胞瘤睾丸生殖细胞肿瘤（tgct）的干细胞，与人胚胎干细胞（ES）具有显著的相似性。在之前的研究中，我们发现EC细胞对低纳摩尔剂量的5-aza脱氧胞苷（5-aza）过敏，这种过敏部分取决于异常高水平的DNA甲基转移酶DNMT3B。我们在这里表明，低剂量5-aza治疗导致NT2/D1细胞的DNA损伤和p53的诱导。此外，低剂量5-aza可导致全局和基因特异性启动子DNA低甲基化。在NT2/D1细胞中，低剂量5-aza诱导了不同于顺铂诱导的p53转录特征，并且还独特地下调了与多能性相关的基因，包括NANOG、SOX2、GDF3和Myc靶基因。p53和多能性特征与5-aza的变化在很大程度上依赖于高水平的DNMT3B。与大多数被5-aza上调的p53靶基因没有表现出DNA低甲基化相反，其他一些被5-aza诱导的基因的启动子甲基化也相应降低。这些基因包括RIN1、SOX15、GPER和TLR4，是tgct中新的候选肿瘤抑制基因。我们的研究表明，NT2/D1细胞对低剂量5-aza的超敏反应是多因素的，涉及p53靶点的激活、多能性基因的抑制和DNA甲基化抑制基因的激活。低剂量5-aza治疗可能是治疗那些由具有胚胎干细胞样特性的细胞维持的肿瘤的一般策略。微阵列数据的GEO编号：GSE42647。
Human embryonal carcinoma (EC) cells are the stem cells of nonseminoma testicular germ cells tumors (TGCTs) and share remarkable similarities to human embryonic stem (ES) cells. In prior work we found that EC cells are hypersensitive to low nanomolar doses of 5-aza deoxycytidine (5-aza) and that this hypersensitivity partially depended on unusually high levels of the DNA methyltransferase, DNMT3B. We show here that low-dose 5-aza treatment results in DNA damage and induction of p53 in NT2/D1 cells. In addition, low-dose 5-aza results in global and gene specific promoter DNA hypomethylation. Low-dose 5-aza induces a p53 transcriptional signature distinct from that induced with cisplatin in NT2/D1 cells and also uniquely downregulates genes associated with pluripotency including NANOG, SOX2, GDF3 and Myc target genes. Changes in the p53 and pluripotency signatures with 5-aza were to a large extent dependent on high levels of DNMT3B. In contrast to the majority of p53 target genes upregulated by 5-aza that did not show DNA hypomethylation, several other genes induced with 5-aza had corresponding decreases in promoter methylation. These genes include RIN1, SOX15, GPER, and TLR4 and are novel candidate tumors suppressors in TGCTs. Our studies suggest that the hypersensitivity of NT2/D1 cells to low-dose 5-aza is multifactorial and involves the combined activation of p53 targets, repression of pluripotency genes, and activation of genes repressed by DNA methylation. Low-dose 5-aza therapy may be a general strategy to treat those tumors that are sustained by cells with embryonic stem-like properties. GEO number for the microarray data: GSE42647.
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影响因子：
23.9
作者：
Fouse, Shaun D.;Shen, Yin;Fan, Guoping
通讯作者：
Fan, Guoping
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Bachman, KE;Rountree, MR;Baylin, SB
通讯作者：
Baylin, SB
DOI：
10.1073/pnas.072067999
发表时间：
2002-04-02
影响因子：
11.1
作者：
Einhorn, LH
通讯作者：
Einhorn, LH
影响因子：
8
作者：
Jiemjit, A.;Fandy, T. E.;Gore, S. D.
通讯作者：
Gore, S. D.