Methyl CpG-binding domain protein 3 mediates cancer-selective cytotoxicity by histone deacetylase inhibitors via differential transcriptional reprogramming in lung cancer cells
Methyl CpG-binding domain protein 3 mediates cancer-selective cytotoxicity by histone deacetylase inhibitors via differential transcriptional reprogramming in lung cancer cells
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DOI：
10.1158/0008-5472.can-05-1092
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发表时间：
2005-12-15
期刊：
影响因子：
11.2
通讯作者：
Lee, JS
中科院分区：
文献类型：
--
作者：
Noh, EJ;Jang, ER;Lee, JS
据报道，历史上的脱乙酰酶抑制剂（HDI）可以抑制癌细胞的生长和存活，同时不影响正常细胞。然而，人们对这种选择性细胞死亡的机制知之甚少。基因表达分析显示，HDI 治疗诱导癌细胞中 p21WAFI/Cip1 上调和 ErbB2 下调，但正常细胞中则不然。 p21(WAF1/Cip1)的过表达和/或ErbB2的沉默增强了癌细胞生长抑制，表明HDI诱导的这些基因的上调/下调在HDI诱导的癌细胞生长抑制中发挥关键作用。最重要的是，我们发现基因沉默因子甲基CpG结合域蛋白3（MBD3）不仅从HDI上调的P21（WAFI/CipI）基因的癌症选择性启动子中释放，而且还被招募到HDI下调的ErbB2基因的启动子上。此外，小干扰RNA沉默MBD3可以消除HDI诱导的肺癌基因调控和生长抑制，但在正常细胞中则不然。总之，我们的结果支持 MBD3 通过癌症差异基因表达在 HDI 诱导的癌症选择性细胞死亡中具有关键潜力。
Historic deacetylase inhibitors (HDI) have been reported to inhibit the growth and survival of cancer cells while leaving normal cells untouched. However, the mechanisms underlying this selective cell death are poorly understood. Gene expression analysis revealed that HDI treatment induced up-regulation of p21WAFI/Cip1 and down-regulation of ErbB2 in cancer cells but not normal cells. Overexpression of p21(WAF1/Cip1) and/or silencing of ErbB2 enhanced cancer cell growth inhibition, suggesting that HDI-induced up-regulation/ down-regulation of these genes play critical roles in HDI-induced growth inhibition of cancer cells. Most importantly, we found that the gene silencing factor methyl CpG-binding domain protein 3 (MBD3) was not, only released from cancer-selective promoter of the HDI up-regulated P21(WAFI/CipI) gene but also recruited to that of the HDI-down-regulated ErbB2 gene. Furthermore, silencing of MBD3 by small interfering RNA abrogated the HDI-induced gene regulation and growth inhibition in lung cancer but not in normal cells. Together, our results support the critical potential of MBD3 in HDI-induced cancer-selective cell death via cancer differential gene expression.