KLF6 Induces Apoptosis in Prostate Cancer Cells through Up-regulation of ATF3
KLF6 Induces Apoptosis in Prostate Cancer Cells through Up-regulation of ATF3
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DOI：
10.1074/jbc.m802515200
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发表时间：
2008-10-31
影响因子：
4.8
通讯作者：
Guo, Bin
中科院分区：
文献类型：
--
作者：
Huang, Xiangwei;Li, Xia;Guo, Bin
KLF6（Kruppel样因子6）是一种锌指转录因子和肿瘤抑制因子，在前列腺癌中经常发生突变。KLF6抑制肿瘤生长并诱导癌细胞凋亡，其机制尚不清楚。在这里，我们表明，KLF6诱导凋亡的前列腺癌细胞的ATF3（转录激活因子3）的表达。KLF6直接结合并激活ATF3启动子。当ATF3在细胞中异位表达时诱导细胞凋亡，而通过小干扰RNA敲低ATF3则阻断KLF6诱导的细胞凋亡。来自临床前列腺癌的KLF6突变体不能激活ATF 3启动子，也不能诱导细胞凋亡。此外，应激条件（暴露于staurosporine和叠氮化钠诱导的缺氧）导致ATF 3表达显著增加并诱导凋亡，而通过小干扰RNA敲低KLF 6则阻断了ATF 3的增加以及在这些条件下诱导的凋亡。因此，ATF3是KLF6诱导前列腺癌细胞凋亡的关键介质。
KLF6 (Kruppel-like factor 6) is a zinc finger transcription factor and a tumor suppressor that is frequently mutated in prostate cancer. KLF6 suppresses tumor growth and induces apoptosis in cancer cells through mechanisms still not defined. Here we show that KLF6 induces apoptosis in prostate cancer cells by ATF3 (activating transcription factor 3) expression. KLF6 binds directly to and activates the ATF3 promoter. ATF3 induced apoptosis when ectopically expressed in cells, whereas knockdown of ATF3 by small interference RNA blocked KLF6-induced apoptosis. KLF6 mutants derived from clinical prostate cancers failed to activate the ATF3 promoter and were unable to induce apoptosis. Furthermore, stress conditions (exposure to staurosporine and hypoxia induced by sodium azide) caused significant increase in ATF3 expression and induced apoptosis, whereas knockdown of KLF6 by small interference RNA blocked the increase of ATF3 as well as the induction of apoptosis in these conditions. Thus, ATF3 is a key mediator of KLF6-induced apoptosis in prostate cancer cells.