School of Biomedical Sciences, University of Queensland, St Lucia, QLD 4072, Australia.
Carcinogenesis. 2010 May;31(5):820-6. doi: 10.1093/carcin/bgq042. Epub 2010 Feb 22.
Human arylamine N-acetyltransferase 1 (NAT1) is a widely distributed protein that has been implicated in a number of different cancers including breast and prostate. Previously, NAT1 gene expression was shown to be androgen dependent, although the effect of androgens was not due to direct activation of the NAT1 promoter. Here, we show that heat shock factor (HSF)1 is induced by androgen in androgen receptor-positive prostate 22Rv1 cells. It also binds to a heat shock element (HSE) in the NAT1 promoter located 776 bp upstream of the transcriptional start site. Mutation of the HSE inhibited androgen responsiveness and prevented direct upregulation of the NAT1 promoter by HSF1. Although HSF2 also bound to the HSE, it did not increase promoter activity. HSF1 induced endogenous NAT1 activity in this cell line in the absence of androgen. This could be attenuated by pretreating cells with HSF1-directed small interfering RNA but not by a scrambled sequence. Our results show that HSF1 is an important transcription factor for induction of NAT1 in human cells and is required for androgen activation of the NAT1 promoter.
人类芳香胺 N-乙酰基转移酶 1（NAT1）是一种广泛分布的蛋白质，与包括乳腺癌和前列腺癌在内的多种不同癌症有关。先前的研究表明，NAT1 基因表达受雄激素依赖，尽管雄激素的作用并非由于 NAT1 启动子的直接激活。在这里，我们显示雄激素可诱导雄激素受体阳性前列腺 22Rv1 细胞中的热休克因子（HSF）1。它还与 NAT1 启动子中的热休克元件（HSE）结合，该元件位于转录起始位点上游 776bp。HSE 的突变抑制了雄激素反应性，并阻止了 HSF1 对 NAT1 启动子的直接上调。尽管 HSF2 也与 HSE 结合，但它不会增加启动子活性。在没有雄激素的情况下，HSF1 在该细胞系中诱导内源性 NAT1 活性。这可以通过用 HSF1 导向的小干扰 RNA 预处理细胞来减弱，但不能用乱序序列来减弱。我们的结果表明，HSF1 是人类细胞中诱导 NAT1 的重要转录因子，并且是雄激素激活 NAT1 启动子所必需的。
