Nucleic Acids Res：维生素A调控前列腺癌机制

英国约克大学癌症科学家们首次证实前列腺癌与维生素A之间存在关联。约克大学癌症研究中心主任Norman Maitland教授发现一种前列腺癌特异性的基因位于视黄酸的控制之下。视黄酸是维生素A的一种衍生物。相关研究结果刊登在<em>Nucleic Acids Research</em>期刊上。

全反式视黄酸已经被用于另一种癌症---急性前骨髓细胞性白血病(acute promyelomcytic leukaemia, APL)的治疗之中。多年来，科学家们已知道人们血液中较低的维生素A水平与前列腺癌相关联，但是没有人知道它的作用机制。

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在这项新的研究中，Maitland教授和同事们发现视黄酸受体表达与前列腺癌实验室模式动物之间存在关联。特别的是，他们研究的这个基因，即前列腺转谷氨酰胺酶(prostate transglutaminase, TGP)，是人基因组28000个基因中众多前列腺特异性基因之一。他们证实TGP基因是由视黄酸信号通路控制着的。

当视黄酸进入前列腺癌细胞之中，它结合到细胞核中三个受体中的一个。这种结合然后就在细胞核内触发一系列分子事件，从而导致TGP基因被关闭或打开。

这项发现意味着人们将可能测试视黄酸(即便是治疗性给药的话)是否能够促进前列腺癌干细胞分化为更加特化的细胞。这一过程被称为分化，能够杀死这些癌干细胞或者让它们对化疗更加敏感。

Maitland教授说，“肿瘤学家一直将诸如视黄酸之类的试剂作为毒性物质来使用。我们需要做的就是使用较低剂量的视黄酸，以便它们能够改变敏感性细胞的性质。然而，它们可能影响正常的干细胞，并且一些细胞可能作出无法预计的反应，因此在开展临床试验之前，我们需要研究到底会发生什么。这也是我们未来的研究重点之一。”
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<a title="" href="http://dx.doi.org/10.1093/nar/gks143" target="_blank">doi: 10.1093/nar/gks143</a>
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<br/><strong>Retinoic acid and androgen receptors combine to achieve tissue specific control of human prostatic transglutaminase expression: a novel regulatory network with broader significance</strong><br/>


Guillermo C. Rivera-Gonzalez, Alastair P. Droop, Helen J. Rippon, Katrin Tiemann, Davide Pellacani, Lindsay J. Georgopoulos and Norman J. Maitland

In the human prostate, expression of prostate-specific genes is known to be directly regulated by the androgen–induced stimulation of the androgen receptor (AR). However, less is known about the expression control of the prostate-restricted TGM4 (hTGP) gene. In the present study we demonstrate that the regulation of the hTGP gene depends mainly on retinoic acid (RA). We provide evidence that the retinoic acid receptor gamma (RAR-G) plays a major role in the regulation of the hTGP gene and that presence of the AR, but not its transcriptional transactivation activity, is critical for hTGP transcription. RA and androgen responsive elements (RARE and ARE) were mapped to the hTGP promoter by chromatin immunoprecipitation (ChIP), which also indicated that the active ARE and RARE sites were adjacent, suggesting that the antagonistic effect of androgen and RA is related to the relative position of binding sites. Publicly available AR and RAR ChIP-seq data was used to find gene potentially regulated by AR and RAR. Four of these genes (CDCA7L, CDK6, BTG1 and SAMD3) were tested for RAR and AR binding and two of them (CDCA7L and CDK6) proved to be antagonistically regulated by androgens and RA confirming that this regulation is not particular of hTGP.

<br/>来源：生物谷

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